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<!DOCTYPE html> <html lang="en" class="no-js"> <head>  <meta http-equiv="Content-Type" content="text/html; charset=utf-8" /> <title>Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme | European Heart Journal | Oxford Academic</title> <script type='text/javascript' defer src='//js.trendmd.com/trendmd.min.js' data-trendmdconfig='{"element":"#trendmd-suggestions"}' class='optanon-category-C0002'></script> <script src="https://ajax.googleapis.com/ajax/libs/jquery/3.7.1/jquery.min.js" type="text/javascript"></script> <script>window.jQuery || document.write('<script src="//oup.silverchair-cdn.com/Themes/Silver/app/js/jquery.3.7.1.min.js" type="text/javascript">\x3C/script>')</script> <script src="//oup.silverchair-cdn.com/Themes/Silver/app/vendor/v-638654880267142888/jquery-migrate-1.4.1.min.js" type="text/javascript"></script> <script type='text/javascript' src='https://platform-api.sharethis.com/js/sharethis.js#property=643701de45aa460012e1032e&product=sop' async='async' class='optanon-category-C0004'></script> <meta name="viewport" content="width=device-width, initial-scale=1, maximum-scale=10" /> <meta http-equiv="X-UA-Compatible" content="IE=Edge" />  <meta name="format-detection" content="telephone=no" />  <link rel="apple-touch-icon" sizes="180x180" href="//oup.silverchair-cdn.com/UI/app/img/v-638654879241847311/apple-touch-icon.png"> <link rel="icon" type="image/png" href="//oup.silverchair-cdn.com/UI/app/img/v-638654879242047735/favicon-32x32.png" sizes="32x32"> <link rel="icon" type="image/png" href="//oup.silverchair-cdn.com/UI/app/img/v-638654879241997236/favicon-16x16.png" sizes="16x16"> <link rel="mask-icon" href="//oup.silverchair-cdn.com/UI/app/img/v-638654879242697268/safari-pinned-tab.svg" color="#001C54"> <link rel="icon" href="//oup.silverchair-cdn.com/UI/app/img/v-638654879242147229/favicon.ico"> <link rel="manifest" href="//oup.silverchair-cdn.com/UI/app/img/v-638654879242447968/manifest.json"> <meta name="msapplication-config" content="//oup.silverchair-cdn.com/UI/app/img/v-638654879241847311/browserconfig.xml"> <meta name="theme-color" content="#002f65"> <link rel="stylesheet" type="text/css" href="//oup.silverchair-cdn.com/UI/app/fonts/icons.css" /> <link rel="stylesheet" type="text/css" href="//oup.silverchair-cdn.com/Themes/Client/app/css/v-638669719594245124/site.min.css" /> <link rel="preload" href="https://fonts.googleapis.com/css?family=Merriweather:300,400,400italic,700,700italic|Source+Sans+Pro:400,400italic,700,700italic" as="style" onload="this.onload=null;this.rel='stylesheet'"> <link href="//oup.silverchair-cdn.com/data/SiteBuilderAssetsOriginals/Live/CSS/journals/v-638647548564311250/global.css" rel="stylesheet" type="text/css" /> <link href="//oup.silverchair-cdn.com/data/SiteBuilderAssets/Live/CSS/eurheartj/v-638563819190395478/Site.css" rel="stylesheet" type="text/css" /> <script> var dataLayer = [{"full_title":"Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme","short_title":"Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme","article_date":"2022-08-26","authors":"Faiez Zannad,João Pedro Ferreira,Javed Butler,Gerasimos Filippatos,James L Januzzi,Mikhail Sumin,Matthias Zwick,Maral Saadati,Stuart J Pocock,Naveed Sattar,Stefan D Anker,Milton Packer","issue_and_volume":"Volume 43 | Issue 48","type":"research-article","online_publication_date":"2022-08-26","access_type":"Open Access","license_type":"cc-by-nc","event_type":"full-text","discipline_ot_level_1":"Medicine and Health","discipline_ot_level_2":"Clinical Medicine","supplier_tag":"SC_Journals","object_type":"Article","taxonomy":"taxId%3a39%7ctaxLabel%3aAcademicSubjects%7cnodeId%3aMED00200%7cnodeLabel%3aCardiovascular+Medicine%7cnodeLevel%3a3","siteid":"eurheartj","authzrequired":"false","doi":"10.1093/eurheartj/ehac495"}]; </script> <script> (function (w, d, s, l, i) { w[l] = w[l] || []; w[l].push({ 'gtm.start': new Date().getTime(), event: 'gtm.js' }); var f = d.getElementsByTagName(s)[0], j = d.createElement(s), dl = l != 'dataLayer' ? 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js-jumplink-list"> <li class="section-jump-link head-1" link-destination="388939850"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939850">Abstract</a> </div> </li> <li class="section-jump-link head-1" link-destination="388939855"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939855">Introduction</a> </div> </li> <li class="section-jump-link head-1" link-destination="388939859"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939859">Methods</a> </div> </li> <li class="section-jump-link head-1" link-destination="388939868"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939868">Results</a> </div> </li> <li class="section-jump-link head-1" link-destination="388939886"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939886">Discussion</a> </div> </li> <li class="section-jump-link head-1" link-destination="388939896"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939896">Conclusion</a> </div> </li> <li class="section-jump-link head-1" link-destination="388939898"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939898">Supplementary material</a> </div> </li> <li class="section-jump-link head-1" link-destination="388939900"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939900">Acknowledgements</a> </div> </li> <li class="section-jump-link head-1" link-destination="388939902"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939902">Funding</a> </div> </li> <li class="section-jump-link head-1" link-destination="388939904"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939904">Data availability</a> </div> </li> <li class="section-jump-link head-1 backReferenceLink" link-destination="388939906"> <div class="section-jump-link__link-wrap"> <a class="js-jumplink scrollTo" href="#388939906">References</a> </div> </li> </ul> </div> </div> <div class="widget widget-ArticleNavLinks widget-instance-OUP_ArticleNavLinks_Article"> <ul class="inline-list"> <li class="prev arrow"> <a href="/eurheartj/article/43/48/4980/6770632">< Previous</a> </li> <li class="next arrow"> <a href="/eurheartj/article/43/48/5003/6808669">Next ></a> </li> </ul> </div> </div> </div> </div> <div class="sticky-toolbar js-sticky-toolbar"></div> <div id="ContentColumn" class="page-column page-column--center"> <div class="article-browse-top article-browse-mobile-nav js-mobile-nav"> <div class="article-browse-mobile-nav-inner js-mobile-nav-inner"> <button class="toggle-left-col toggle-left-col__article btn-as-link"> Article Navigation </button> </div> </div> <div class="article-browse-top article-browse-mobile-nav mobile-sticky-toolbar js-mobile-nav-sticky"> <div class="article-browse-mobile-nav-inner"> <button class="toggle-left-col toggle-left-col__article btn-as-link"> Article Navigation </button> </div> </div> <div class="content-inner-wrap"> <div class="widget widget-ArticleTopInfo widget-instance-OUP_ArticleTop_Info_Widget"> <div class="module-widget article-top-widget"> <div class="access-state-logos all-viewports"> <span class="journal-info__format-label">Journal Article</span> </div> <div class="widget-items"> <div class="title-wrap"> <h1 class="wi-article-title article-title-main accessible-content-title at-articleTitle"> Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme <i class='icon-availability_open' title='Open Access' ></i> </h1> </div> <div class="wi-authors at-ArticleAuthors"> <div class="al-authors-list"> <div class="meta-authors--limited"> <span class="al-author-name js-flyout-wrap"> <button type="button" class="linked-name js-linked-name-trigger btn-as-link">Faiez Zannad</button><span class='delimiter'>, </span> <span class="al-author-info-wrap arrow-up"> <div class="info-card-author authorInfo_OUP_ArticleTop_Info_Widget"> <div class="name-role-wrap"> <div class="info-card-name"> Faiez Zannad <span class="info-card-footnote"><span class="xrefLink" id="jumplink-ehac495-cor1"></span><a href="javascript:;" reveal-id="ehac495-cor1" data-open="ehac495-cor1" class="link link-ref link-reveal xref-default"></a></span> </div> </div> <div class="info-card-affilitation"> <div class="aff"><div class="institution">Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists)</div>, <div class="addr-line">5, rue du Morvan, 54500 Vandoeuvre-Les-Nancy</div>, <div class="country">France</div></div> </div> <div class="info-author-correspondence"> <div content-id="ehac495-cor1">Corresponding author. Tel: +33 3 83 15 73 15, Fax: +33 3 83 15 73 24, Emails: <a href="mailto:f.zannad@chru-nancy.fr" target="_blank">f.zannad@chru-nancy.fr</a>; <a href="mailto:j.ferreira@chru-nancy.fr" target="_blank">j.ferreira@chru-nancy.fr</a></div> </div> <div class="info-card-location"> <a id="contrib-orcid-0000-0001-7456-1570" href="https://orcid.org/0000-0001-7456-1570"> <img class="orchid-icon" alt="ORCID logo" aria-hidden="true" src="//oup.silverchair-cdn.com/Themes/Silver/app/img/mini-icon.png"/>  https://orcid.org/0000-0001-7456-1570 </a> </div> <div class="info-card-search-label"> Search for other works by this author on: </div> <div class="info-card-search info-card-search-internal"> <a href="/eurheartj/search-results?f_Authors=Faiez+Zannad" rel="nofollow">Oxford Academic</a> </div> <div class="info-card-search info-card-search-pubmed"> <a href="http://www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=Zannad F">PubMed</a> </div> <div class="info-card-search info-card-search-google"> <a href="http://scholar.google.com/scholar?q=author:%22Zannad Faiez%22">Google Scholar</a> </div> </div> </span> </span> <span class="al-author-name js-flyout-wrap"> <button type="button" class="linked-name js-linked-name-trigger btn-as-link">João Pedro Ferreira</button><span class='delimiter'>, </span> <span class="al-author-info-wrap arrow-up"> <div class="info-card-author authorInfo_OUP_ArticleTop_Info_Widget"> <div class="name-role-wrap"> <div class="info-card-name"> João Pedro Ferreira <span class="info-card-footnote"><span class="xrefLink" id="jumplink-ehac495-cor1"></span><a href="javascript:;" reveal-id="ehac495-cor1" data-open="ehac495-cor1" class="link link-ref link-reveal xref-default"></a></span> </div> </div> <div class="info-card-affilitation"> <div class="aff"><div class="institution">Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists)</div>, <div class="addr-line">5, rue du Morvan, 54500 Vandoeuvre-Les-Nancy</div>, <div class="country">France</div></div><div class="aff"><div class="institution">Cardiovascular R&D Centre-UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto</div>, <div class="addr-line">Alameda Professor Hernâni Monteiro 4200-319 Porto</div>, <div class="country">Portugal</div></div><div class="aff"><div class="institution">Internal Medicine Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, R. Conceição Fernandes S/N</div>, <div class="addr-line">4434-502 Vila Nova de Gaia</div>, <div class="country">Portugal</div></div> </div> <div class="info-author-correspondence"> <div content-id="ehac495-cor1">Corresponding author. Tel: +33 3 83 15 73 15, Fax: +33 3 83 15 73 24, Emails: <a href="mailto:f.zannad@chru-nancy.fr" target="_blank">f.zannad@chru-nancy.fr</a>; <a href="mailto:j.ferreira@chru-nancy.fr" target="_blank">j.ferreira@chru-nancy.fr</a></div> </div> <div class="info-card-location"> <a id="contrib-orcid-0000-0002-2304-6138" href="https://orcid.org/0000-0002-2304-6138"> <img class="orchid-icon" alt="ORCID logo" aria-hidden="true" src="//oup.silverchair-cdn.com/Themes/Silver/app/img/mini-icon.png"/>  https://orcid.org/0000-0002-2304-6138 </a> </div> <div class="info-card-search-label"> Search for other works by this author on: </div> <div class="info-card-search info-card-search-internal"> <a href="/eurheartj/search-results?f_Authors=Jo%c3%a3o+Pedro+Ferreira" rel="nofollow">Oxford Academic</a> </div> <div class="info-card-search info-card-search-pubmed"> <a href="http://www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=Ferreira J">PubMed</a> </div> <div class="info-card-search info-card-search-google"> <a href="http://scholar.google.com/scholar?q=author:%22Ferreira João Pedro%22">Google Scholar</a> </div> </div> </span> </span> <span class="al-author-name js-flyout-wrap"> <button type="button" class="linked-name js-linked-name-trigger btn-as-link">Javed Butler</button><span class='delimiter'>, </span> <span class="al-author-info-wrap arrow-up"> <div class="info-card-author authorInfo_OUP_ArticleTop_Info_Widget"> <div class="name-role-wrap"> <div class="info-card-name"> Javed Butler </div> </div> <div class="info-card-affilitation"> <div class="aff"><div class="institution">Heart and Vascular Research, Baylor Scott and White Research Institute</div>, <div class="addr-line">34 Live Oak St Ste 501, Dallas, TX 75204</div>, <div class="country">USA</div></div><div class="aff"><div class="institution">University of Mississippi Medical Center</div>, <div class="addr-line">2500 North State Street Jackson, MS 39216</div>, <div class="country">USA</div></div> </div> <div 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<span class="al-author-name-more js-flyout-wrap"> <button type="button" class="linked-name js-linked-name-trigger btn-as-link">Stefan D Anker</button><span class='delimiter'>, </span> <span class="al-author-info-wrap arrow-up"> <div class="info-card-author authorInfo_OUP_ArticleTop_Info_Widget"> <div class="name-role-wrap"> <div class="info-card-name"> Stefan D Anker </div> </div> <div class="info-card-affilitation"> <div class="aff"><div class="institution">Department of Cardiology (CVK) Berlin Institute of Health Center for Regenerative Therapies (BCRT) German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Charité, Campus Virchow-Klinikum</div>, <div class="addr-line">Augustenburger Platz 1, D-13353 Berlin</div>, <div class="country">Germany</div></div><div class="aff"><div class="institution">Institute of Heart Diseases, Wroclaw Medical University</div>, <div class="addr-line">Borowska Street 213, 50-556 Warsaw</div>, <div 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class="footnote-compatibility">Faiez Zannad and João Pedro Ferreira Co-first authors.</p></div></span></div> </div> <div class="widget widget-SingleSection widget-instance-OUP_FootnoteSection"> <div content-id="ehac495-FM2" class="footnote"><span class="fn"><div class="footnote-content"><p class="footnote-compatibility"><strong>Conflict of interest:</strong> F.Z. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer and, Cellprothera, other from CVCT, and Cardiorenal, outside the submitted work. J.P.F. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work. J.B. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave and Vifor, outside the submitted work. G.F. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Medtronic, Vifor, Servier, Novartis, Bayer, Amgen and Boehringer Ingelheim, outside the submitted work. J.L.J., a Trustee of the American College of Cardiology, a Board member of Imbria Pharmaceuticals, has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics, consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics, and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia and Takeda. M.S. and M.Z. are employees of Boehringer Ingelheim. M.S. is an employee of Elderbrook Solutions. S.J.P. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work. S.A. reports personal fees from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Abbott Vascular, Vifor, personal fees from Bayer, Boehringer Ingelheim, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis and Servier, outside the submitted work. N.S. has consulted for Amgen, Astrazeneca, Boehringer Ingelheim, Eli-Lilly, Hanmi Pharmaceuticals, Novo Nordisk, Novartis, Novartis, Sanofi and Pfizer and received grant support from Boehringer Ingelheim. S.D.A. reports grants and personal fees from Vifor Int. and Abbott Vascular, and personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor Int. Personal fees from Boehringer Ingelheim during the conduct of the study. M.P. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Abbvie, Actavis, Altimmune, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, Salamandra, outside the submitted work.</p></div></span></div> </div> </div> <a class="js-linked-footnotes" href="javascript:;">Author Notes</a> </div> </div> </div> <div class="pub-history-wrap clearfix js-history-dropdown-wrap"> <div class="pub-history-row clearfix"> <div class="ww-citation-primary"><em>European Heart Journal</em>, Volume 43, Issue 48, 21 December 2022, Pages 4991–5002, <a href='https://doi.org/10.1093/eurheartj/ehac495'>https://doi.org/10.1093/eurheartj/ehac495</a></div> </div> <div class="pub-history-row clearfix"> <div class="ww-citation-date-wrap"> <div class="citation-label">Published:</div> <div class="citation-date">26 August 2022</div> </div> <a href="javascript:;" class="history-label 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</div> </div> <div id="ContentTab" class="content active"> <div class="widget widget-ArticleFulltext widget-instance-OUP_Article_FullText_Widget"> <div class="module-widget"> <div class="widget-items" data-widgetname="ArticleFulltext"> <h2 scrollto-destination=388939850 id="388939850" class="abstract-title js-splitscreen-abstract-title" >Abstract</h2> <section class="abstract"><div class=" sec"><div class="title">Aims</div><p class="chapter-para">Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics.</p></div><div class=" sec"><div class="title">Methods and results</div><p class="chapter-para">Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by ≥10% with a false discovery rate <1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption.</p></div><div class=" sec"><div class="title">Conclusions</div><p class="chapter-para">Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.</p></div></section> <div class="article-metadata-panel clearfix at-ArticleMetadata"></div> <div id="388939851"></div> <section class="abstract abstractBorder graphicalAbstract"><div class="
 block-child-p
 js-p-fig-section"><span id="ehac495ga1"></span><div data-id="ehac495ga1" data-content-id="ehac495ga1" class="fig fig-section" swap-content-for-modal="true"><div class="graphic-wrap"><img class="content-image" src="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/m_ehac495ga1.jpeg?Expires=1735388495&Signature=uKzUyEVq2qBQWJBD0QEWO6SrAXa5JRBGBXuloLgHTpOmQJ~QzAqL7duHigN21A~l~m4DNK9JxyrEFX4cvGRzSnvZziH5GM9T7OnulH6hS9A5OmJjh9-u7oC1xH4tW74AxNtunP57gv6RQkz8tGypL0B1LOo99IX9jt-vHhpIZSrC4FrpjsnkhXYCiTiAkjN91gi9J1OYRnuMNjNQCuRhHoJhxau4gvfYtDAYK--23B3blafrzAbhnfxM8xZTSjnHetUptH5q5DymOm9OIw-95VjVeez4z4BycT0n7xv8HpgXs0YaUGgiLF7pdyIxJeu5-kfzp5XxCm98P~dz6weoTQ__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA" alt="Favourable biological and cellular actions of differentially expressed proteins in the heart and kidney. IGFBP1, insulin-like growth factor-binding protein 1; TfR1, transferrin receptor protein 1; EPO, erythropoietin; TGM2, protein-glutamine gamma-glutamyltransferase 2; TMSB10, thymosin beta-10; uMtCK, mitochondrial creatine kinase U-type; IGFBP4, insulin-like growth factor-binding protein 4; EpCAM, epithelial cell adhesion molecule; PLA2, phospholipase A2; ANGPTL4, angiopoietin-related protein 4; RBP2, retinol-binding protein 2; CCN5, CCN family member 5; FST, follistatin; Mdk, midkine; GUCA, guanylin." data-path-from-xml="ehac495ga1.tif"><div class="graphic-bottom"><div class="label fig-label" id="label-388939851">Structured Graphical Abstract</div><div class="caption fig-caption"><p class="chapter-para">Favourable biological and cellular actions of differentially expressed proteins in the heart and kidney. IGFBP1, insulin-like growth factor-binding protein 1; TfR1, transferrin receptor protein 1; EPO, erythropoietin; TGM2, protein-glutamine gamma-glutamyltransferase 2; TMSB10, thymosin beta-10; uMtCK, mitochondrial creatine kinase U-type; IGFBP4, insulin-like growth factor-binding protein 4; EpCAM, epithelial cell adhesion molecule; PLA2, phospholipase A2; ANGPTL4, angiopoietin-related protein 4; RBP2, retinol-binding protein 2; CCN5, CCN family member 5; FST, follistatin; Mdk, midkine; GUCA, guanylin.</p></div><div class="ajax-articleAbstract-exclude-regex fig-orig original-slide figure-button-wrap"><a class="fig-view-orig js-view-large at-figureViewLarge openInAnotherWindow" role="button" aria-describedby="label-388939851" href="/view-large/figure/388939851/ehac495ga1.tif?itm_medium=graphical+abstract+image&itm_content=open+image&itm_source=http://academic.oup.com/eurheartj/article/43/48/4991/6676779&itm_campaign=graphical+abstract" data-path-from-xml="ehac495ga1.tif" target="_blank">Open in new tab</a><a class="download-slide" role="button" aria-describedby="label-388939851" data-section="388939851" href="/DownloadFile/DownloadImage.aspx?image=https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495ga1.jpeg?Expires=1735388495&Signature=Xkx5LZxS8ALXtUDJGzpVHFyjmEQ0TZ7GUDwSuITxONK9yvk~~-YmoPfUm~sGQ9~MP6j57~Y1sTiXggjyCPq4GwDQPCx2W3EFyWASHLEOsndhPgDe-4E5jGlOFXT4DibXtyyj8~ckMQv3JpACxNaQzby4uFwTQELDDQRFJNOOudmNogGHW5y-zWLWR33TdMumdn1--4~YAUWZbxeqBr0yOv5-6aMSEGJUpgKNvgz0ssiAy85vWyvT9LidLCk3S4ECBt3rjBF8IqWr6whKPZIxwfLHFrS38uoIsRRZ-JzDQ5AaheRml9XDeCD95tXpUbTfMCCtUjBoZOhf97PHBYzjpA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA&sec=388939851&ar=6676779&xsltPath=~/UI/app/XSLT&imagename=&siteId=5375&itm_medium=graphical+abstract+image&itm_content=download+button&itm_source=http://academic.oup.com/eurheartj/article/43/48/4991/6676779&itm_campaign=graphical+abstract" data-path-from-xml="ehac495ga1.tif">Download slide</a></div></div></div></div></div></section> <div class="article-metadata-panel clearfix at-ArticleMetadata"></div> <div class="kwd-group"><a class="kwd-part kwd-main" href="javascript:;" data-keyword=""Heart failure"">Heart failure</a>, <a class="kwd-part kwd-main" href="javascript:;" data-keyword="Proteomics">Proteomics</a>, <a class="kwd-part kwd-main" href="javascript:;" data-keyword=""SGLT2 inhibitors"">SGLT2 inhibitors</a>, <a class="kwd-part kwd-main" href="javascript:;" data-keyword=""Differentially expressed proteins"">Differentially expressed proteins</a></div><p class="chapter-para"><strong>See the editorial comment for this article ‘SGLT2 inhibitors in heart failure: insights from plasma proteomics’, by Clemens Gutmann <em>et al</em>., <a class="link link-uri openInAnotherWindow" href="https://doi.org/10.1093/eurheartj/ehac624" target="_blank">https://doi.org/10.1093/eurheartj/ehac624</a>.</strong></p> <h2 scrollto-destination=388939855 id="388939855" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s0>Introduction</h2> <p class="chapter-para">Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes across a wide range of high-risk patients, including those with Type 2 diabetes, chronic kidney disease, and heart failure with a reduced or preserved ejection fraction.<sup><span class="xrefLink" id="jumplink-ehac495-B1"></span><a href="javascript:;" reveal-id="ehac495-B1" data-open="ehac495-B1" class="link link-ref link-reveal xref-bibr">1</a></sup> These benefits have been characterized by a decrease in the risk of cardiovascular mortality and heart failure hospitalizations and a reduction in major adverse renal events.<sup><span class="xrefLink" id="jumplink-ehac495-B2"></span><a href="javascript:;" reveal-id="ehac495-B2" data-open="ehac495-B2" class="link link-ref link-reveal xref-bibr">2</a></sup></p><p class="chapter-para">The underlying mechanisms by which SGLT2 inhibitors improve heart failure and renal outcomes are incompletely understood. Recent evidence suggests that SGLT2 inhibitors may induce a state of starvation mimicry, characterized by enhanced nutrient deprivation signalling and autophagic flux, which leads to an improvement in mitochondrial function, a decrease in oxidative stress, and suppression of proinflammatory and profibrotic pathways.<sup><span class="xrefLink" id="jumplink-ehac495-B3"></span><a href="javascript:;" reveal-id="ehac495-B3" data-open="ehac495-B3" class="link link-ref link-reveal xref-bibr">3</a></sup> It has also been hypothesized that SGLT2 inhibitors may decrease the activity of sodium–hydrogen exchangers in the heart and kidneys, which may reduce intracellular sodium in cardiomyocytes and promote urinary sodium excretion.<sup><span class="xrefLink" id="jumplink-ehac495-B4"></span><a href="javascript:;" reveal-id="ehac495-B4" data-open="ehac495-B4" class="link link-ref link-reveal xref-bibr">4</a></sup> Mediation analyses have identified increases in haemoglobin and decreases in uric acid as statistical intermediaries of the benefits of SGLT2 inhibitors on heart failure and renal outcomes.<sup><span class="xrefLink" id="jumplink-ehac495-B5"></span><a href="javascript:;" reveal-id="ehac495-B5" data-open="ehac495-B5" class="link link-ref link-reveal xref-bibr">5</a>,<span class="xrefLink" id="jumplink-ehac495-B6"></span><a href="javascript:;" reveal-id="ehac495-B6" data-open="ehac495-B6" class="link link-ref link-reveal xref-bibr">6</a></sup> Changes in haemoglobin and uric acid may reflect the effects of enhanced nutrient deprivation signalling on erythropoietin production and the effects of augmented autophagic flux on oxidative stress.<sup><span class="xrefLink" id="jumplink-ehac495-B3"></span><a href="javascript:;" reveal-id="ehac495-B3" data-open="ehac495-B3" class="link link-ref link-reveal xref-bibr">3</a>,<span class="xrefLink" id="jumplink-ehac495-B7"></span><a href="javascript:;" reveal-id="ehac495-B7" data-open="ehac495-B7" class="link link-ref link-reveal xref-bibr">7</a></sup></p><p class="chapter-para">We performed large-scale proteomic analyses of biosamples collected in the EMPEROR-Reduced and EMPEROR-Preserved trials before and following short- and long-term treatment with empagliflozin to gain insights into the potential mechanisms of action of SGLT2 inhibitors in patients with chronic heart failure.</p> <h2 scrollto-destination=388939859 id="388939859" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s1>Methods</h2> <h3 scrollto-destination=388939860 id="388939860" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s1.1>Study populations and biosampling</h3> <p class="chapter-para">A total of 9718 patients were randomized into the EMPEROR-Reduced (<em>n</em> = 3730) and EMPEROR-Preserved (<em>n</em> = 5988) trials. Participation in sampling for biobanking of plasma, serum, DNA, and urine was voluntary and not a prerequisite for participation in the trials. Biosamples were collected only if a separate informed consent had been signed, in accordance with local ethical and regulatory requirements. The countries that participated in the biobanking substudy and the methodology of sample collection are described in <span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Supplementary material online</a></span>, <em><span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Methods S1</a></span></em>.</p><p class="chapter-para">In EMPEROR-Reduced, 3831 patients gave consent for the collection of biosamples, and of these, 1963 patients had samples available at baseline (i.e. before randomization) and at one or both on-treatment sampling visits (at Week 12 or Week 52). In EMPEROR-Preserved, of the 3067 patients who gave consent for the collection of biosamples, 1463 patients had samples available at baseline and at one or both on-treatment sampling visits (at Week 12 or Week 52). The plasma samples of 600 patients (out of 1963) in EMPEROR-Reduced and of 539 (out of 1463) in EMPEROR-Preserved were randomly selected, and patients were stratified by treatment assignment and data availability. This sample size was determined by budgetary constraints. A total of 599 patients (out of the 600) in EMPEROR-Reduced and 535 (out of 539) in EMPEROR-Preserved had good quality samples with available data both at baseline and at one or both post-randomization visits; thus, a total of 1134 patients were included in the pooled analysis (EMPEROR-Pooled), see <span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Supplementary material online</a></span>, <em><span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Methods S2</a></span></em>.</p><p class="chapter-para">In these 1134 patients, measurements of circulating proteins were performed using the Olink® Explore 1536 platform, which utilizes proximity extension assay (PEA) technology with a dual-recognition DNA-coupled readout, in which oligonucleotide-labelled antibody probe pairs bind to their respective targets.<sup><span class="xrefLink" id="jumplink-ehac495-B8"></span><a href="javascript:;" reveal-id="ehac495-B8" data-open="ehac495-B8" class="link link-ref link-reveal xref-bibr">8</a></sup> The Olink® Explore 1536 platform consists of 1472 protein assays and 64 internal controls, and divided into four 384-plex panels, and in each panel, overlapping assays of interleukin-6, interleukin-8, and tumour necrosis factor-α are included as an additional quality control. The platform provides log<sub>2</sub> normalized protein expression values with relative quantification. The performance of the assays was blinded to the treatment allocation. Samples were allocated in a random order to avoid any systematic influence of study or timepoint. Protein expression values were missing when samples failed quality control (as specified by the manufacturer), and missing values were not imputed. Proteins that were below the limit of detection in >33% of baseline samples were excluded from the analysis. A total of 1283 proteins were evaluated.</p> <h3 scrollto-destination=388939864 id="388939864" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s1.2>Statistical and bioinformatical analysis</h3> <p class="chapter-para">Differences in the level of proteins were assessed using mixed models for repeated measurements, in which we calculated the between-group difference (empagliflozin vs. placebo) in the change in plasma concentrations for each protein from baseline to Week 12 and Week 52, while adjusting for the baseline covariates that had been pre-specified in the statistical plan for each trial [i.e. age, sex, geographical region, diabetes, left ventricular ejection fraction, estimated glomerular filtration rate (eGFR)]. We also pre-specified an adjustment for the baseline protein expression and trial assignment (EMPEROR-Reduced and EMPEROR-Preserved). The change from baseline in eGFR was included as a covariate in a <em>post hoc</em> sensitivity analysis.</p><p class="chapter-para">We identified differentially expressed proteins as those fulfilling two independent criteria: (i) proteins with |log<sub>2</sub> fold change| >log<sub>2</sub>(1.1), corresponding to a ≥10% increase from baseline (log<sub>2</sub> fold change >0.1375) or a symmetric >9.09% decrease from baseline and (ii) a false discovery rate <em>q</em>-value (FDR<em>q</em>) <1%, which applies a Benjamini–Hochberg correction to the raw <em>P</em>-value, in order to minimize inflation of a false-positive error rate due to multiplicity of comparisons.<sup><span class="xrefLink" id="jumplink-ehac495-B9"></span><a href="javascript:;" reveal-id="ehac495-B9" data-open="ehac495-B9" class="link link-ref link-reveal xref-bibr">9</a></sup> Significance of differences between treatment effects at Weeks 12 and 52 were investigated by a treatment-by-visit interaction term in the model.</p><p class="chapter-para">All proteins measured in the Olink® platform are known to exert diverse function across many biological domains. We initially grouped differentially expressed proteins according to their reported actions in oncology, but these groupings had little meaning in cardiology and nephrology. Therefore, we performed an extensive biomedical literature search to identify the biological effects of differentially expressed proteins in the heart and kidneys.</p> <h2 scrollto-destination=388939868 id="388939868" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s2>Results</h2> <h3 scrollto-destination=388939869 id="388939869" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s2.1>Patient characteristics</h3> <p class="chapter-para">The 1134 patients had a mean age of 70 years, 32% were women, 85% were White, and 57% were recruited in Europe. In addition, 48% had Type 2 diabetes, the mean left ventricular ejection fraction was 40%, and the mean eGFR was 61 mL/min/1.73 m<sup>2</sup>. When the 1134 patients whose biosamples were analysed were compared with the 8584 patients who were randomized in the EMPEROR trial but were not represented in the current analyses, patients not in the current analysis were more likely to be women (37 vs. 32%), less likely to be White (72 vs. 85%), or from Europe (40 vs. 57%), and had a higher ejection fraction (45 vs. 40%), refer <span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Supplementary material online</a></span>, <em><span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Table S1</a></span></em>.</p> <h3 scrollto-destination=388939871 id="388939871" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s2.2>Differentially expressed proteins at Week 12</h3> <p class="chapter-para">Based on our pre-specified criteria and covariate adjustment, 32 of 1283 proteins fulfilled our threshold for being differentially expressed at Week 12; all were increased by ≥10% (log<sub>2</sub> fold change >0.1375) and had a false discovery rate <1% (corresponding generally to a raw <em>P</em>-value <0.0007 for the difference between empagliflozin and placebo), <em><span class="xrefLink" id="jumplink-ehac495-T1"></span><a href="javascript:;" reveal-id="ehac495-T1" data-open="ehac495-T1" class="link link-reveal link-table xref-fig">Table 1</a></em>.</p> <a id="388939873" scrollto-destination="388939873"></a> <div content-id="ehac495-T1" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="ehac495-T1" data-id="ehac495-T1"><span class="label title-label" id="label-96664">Table 1</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/388939873" aria-describedby="label-96664"> Open in new tab </a></div><div class="caption caption-id-" id="caption-96664"><p class="chapter-para">Differential expressed proteins (empagliflozin vs. placebo) at Week 12</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-96664" aria-describedby="
 caption-96664"><thead><tr><th rowspan="2">Protein<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">UniprotID<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="2">Before adjustment for change in eGFR<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="2">After adjustment for change in eGFR<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Empagliflozin vs. placebo, log<sub>2</sub> fold change (95% CI)<span aria-hidden="true" style="display: none;"> . </span></th><th>False discovery rate (%)<span aria-hidden="true" style="display: none;"> . </span></th><th>Empagliflozin vs. placebo, log<sub>2</sub> fold change (95% CI)<span aria-hidden="true" style="display: none;"> . </span></th><th>False discovery rate (%)<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>IGFBP1</td><td>P08833</td><td>0.27 (0.14–0.40)</td><td>0.16</td><td>0.25 (0.13–0.38)</td><td>0.55</td></tr><tr><td>TfR1</td><td>P02786</td><td>0.26 (0.19–0.32)</td><td><0.0001</td><td>0.25 (0.18–0.32)</td><td><0.001</td></tr><tr><td>CA2</td><td>P00918</td><td>0.25 (0.11–0.39)</td><td>0.81</td><td>0.26 (0.12–0.40)</td><td>1.02</td></tr><tr><td>EPO</td><td>P01588</td><td>0.25 (0.11–0.38)</td><td>0.65</td><td>0.24 (0.10–0.37)</td><td>1.53</td></tr><tr><td>TGM2</td><td>P21980</td><td>0.25 (0.11–0.38)</td><td>0.60</td><td>0.25 (0.12–0.38)</td><td>1.02</td></tr><tr><td>TMSB10</td><td>P63313</td><td>0.22 (0.11–0.34)</td><td>0.43</td><td>0.19 (0.08–0.31)</td><td>2.18</td></tr><tr><td>uMtCK</td><td>P12532</td><td>0.21 (0.10–0.32)</td><td>0.43</td><td>0.22 (0.11–0.33)</td><td>0.69</td></tr><tr><td>IGFBP4</td><td>P22692</td><td>0.21 (0.13–0.30)</td><td>0.01</td><td>0.17 (0.09–0.25)</td><td>0.31</td></tr><tr><td>AFABP4</td><td>P15090</td><td>0.21 (0.12–0.29)</td><td>0.02</td><td>0.17 (0.09–0.25)</td><td>0.31</td></tr><tr><td>CCL18</td><td>P55774</td><td>0.20 (0.11–0.29)</td><td>0.08</td><td>0.19 (0.10–0.28)</td><td>0.31</td></tr><tr><td>Follistatin</td><td>P19883</td><td>0.20 (0.13–0.26)</td><td><0.0001</td><td>0.19 (0.12–0.26)</td><td><0.0001</td></tr><tr><td>Midkine</td><td>P21741</td><td>0.20 (0.11–0.29)</td><td>0.14</td><td>0.18 (0.09–0.27)</td><td>0.55</td></tr><tr><td>Guanylin</td><td>Q02747</td><td>0.20 (0.13–0.26)</td><td><0.0001</td><td>0.17 (0.11–0.23)</td><td><0.001</td></tr><tr><td>SPINK1</td><td>P00995</td><td>0.20 (0.13–0.26)</td><td><0.01</td><td>0.16 (0.10–0.23)</td><td>0.02</td></tr><tr><td>Rarres2</td><td>Q99969</td><td>0.19 (0.10–0.29)</td><td>0.18</td><td>0.17 (0.08–0.27)</td><td>0.96</td></tr><tr><td>CNDP1</td><td>Q96KN2</td><td>0.19 (0.11–0.28)</td><td>0.07</td><td>0.19 (0.11–0.27)</td><td>0.19</td></tr><tr><td>EpCAM</td><td>P16422</td><td>0.19 (0.10–0.28)</td><td>0.17</td><td>0.20 (0.10–0.29)</td><td>0.29</td></tr><tr><td>CCL27</td><td>Q9Y4X3</td><td>0.19 (0.09–0.29)</td><td>0.61</td><td>0.17 (0.07–0.27)</td><td>2.16</td></tr><tr><td>SRCR</td><td>Q8WTU2</td><td>0.18 (0.09–0.27)</td><td>0.21</td><td>0.18 (0.09–0.27)</td><td>0.48</td></tr><tr><td>PLA2</td><td>P14555</td><td>0.18 (0.08–0.27)</td><td>0.54</td><td>0.16 (0.07–0.26)</td><td>2.07</td></tr><tr><td>Promotilin</td><td>P12872</td><td>0.18 (0.09–0.26)</td><td>0.26</td><td>0.16 (0.08–0.25)</td><td>1.02</td></tr><tr><td>ANGPTL4</td><td>Q9BY76</td><td>0.17 (0.11–0.23)</td><td>0.00</td><td>0.16 (0.09–0.22)</td><td>0.01</td></tr><tr><td>RBP2</td><td>P50120</td><td>0.17 (0.07–0.26)</td><td>0.98</td><td>0.15 (0.05–0.24)</td><td>4.02</td></tr><tr><td>Uromodulin</td><td>P07911</td><td>0.16 (0.10–0.22)</td><td><0.0001</td><td>0.18 (0.12–0.23)</td><td><0.0001</td></tr><tr><td>Cystatin-F</td><td>O76096</td><td>0.16 (0.07–0.25)</td><td>0.63</td><td>0.15 (0.06–0.24)</td><td>1.89</td></tr><tr><td>CCN5</td><td>O76076</td><td>0.15 (0.08–0.22)</td><td>0.14</td><td>0.14 (0.07–0.21)</td><td>0.69</td></tr><tr><td>CCL16</td><td>O15467</td><td>0.15 (0.08–0.22)</td><td>0.19</td><td>0.13 (0.06–0.21)</td><td>1.02</td></tr><tr><td>Osteopontin</td><td>P10451</td><td>0.14 (0.08–0.21)</td><td>0.18</td><td>0.13 (0.06–0.20)</td><td>1.02</td></tr><tr><td>ANGPTL2</td><td>Q9UKU9</td><td>0.14 (0.07–0.22)</td><td>0.54</td><td>0.14 (0.06–0.21)</td><td>1.16</td></tr><tr><td>NPDC1</td><td>Q9NQX5</td><td>0.14 (0.08–0.21)</td><td>0.07</td><td>0.11 (0.06–0.17)</td><td>1.02</td></tr><tr><td>Elafin</td><td>P19957</td><td>0.14 (0.07–0.21)</td><td>0.44</td><td>0.11 (0.04–0.18)</td><td>3.96</td></tr><tr><td>Cystatin-M</td><td>Q15828</td><td>0.14 (0.08–0.20)</td><td>0.10</td><td>0.11 (0.05–0.17)</td><td>1.02</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th rowspan="2">Protein<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">UniprotID<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="2">Before adjustment for change in eGFR<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="2">After adjustment for change in eGFR<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Empagliflozin vs. placebo, log<sub>2</sub> fold change (95% CI)<span aria-hidden="true" style="display: none;"> . </span></th><th>False discovery rate (%)<span aria-hidden="true" style="display: none;"> . </span></th><th>Empagliflozin vs. placebo, log<sub>2</sub> fold change (95% CI)<span aria-hidden="true" style="display: none;"> . </span></th><th>False discovery rate (%)<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>IGFBP1</td><td>P08833</td><td>0.27 (0.14–0.40)</td><td>0.16</td><td>0.25 (0.13–0.38)</td><td>0.55</td></tr><tr><td>TfR1</td><td>P02786</td><td>0.26 (0.19–0.32)</td><td><0.0001</td><td>0.25 (0.18–0.32)</td><td><0.001</td></tr><tr><td>CA2</td><td>P00918</td><td>0.25 (0.11–0.39)</td><td>0.81</td><td>0.26 (0.12–0.40)</td><td>1.02</td></tr><tr><td>EPO</td><td>P01588</td><td>0.25 (0.11–0.38)</td><td>0.65</td><td>0.24 (0.10–0.37)</td><td>1.53</td></tr><tr><td>TGM2</td><td>P21980</td><td>0.25 (0.11–0.38)</td><td>0.60</td><td>0.25 (0.12–0.38)</td><td>1.02</td></tr><tr><td>TMSB10</td><td>P63313</td><td>0.22 (0.11–0.34)</td><td>0.43</td><td>0.19 (0.08–0.31)</td><td>2.18</td></tr><tr><td>uMtCK</td><td>P12532</td><td>0.21 (0.10–0.32)</td><td>0.43</td><td>0.22 (0.11–0.33)</td><td>0.69</td></tr><tr><td>IGFBP4</td><td>P22692</td><td>0.21 (0.13–0.30)</td><td>0.01</td><td>0.17 (0.09–0.25)</td><td>0.31</td></tr><tr><td>AFABP4</td><td>P15090</td><td>0.21 (0.12–0.29)</td><td>0.02</td><td>0.17 (0.09–0.25)</td><td>0.31</td></tr><tr><td>CCL18</td><td>P55774</td><td>0.20 (0.11–0.29)</td><td>0.08</td><td>0.19 (0.10–0.28)</td><td>0.31</td></tr><tr><td>Follistatin</td><td>P19883</td><td>0.20 (0.13–0.26)</td><td><0.0001</td><td>0.19 (0.12–0.26)</td><td><0.0001</td></tr><tr><td>Midkine</td><td>P21741</td><td>0.20 (0.11–0.29)</td><td>0.14</td><td>0.18 (0.09–0.27)</td><td>0.55</td></tr><tr><td>Guanylin</td><td>Q02747</td><td>0.20 (0.13–0.26)</td><td><0.0001</td><td>0.17 (0.11–0.23)</td><td><0.001</td></tr><tr><td>SPINK1</td><td>P00995</td><td>0.20 (0.13–0.26)</td><td><0.01</td><td>0.16 (0.10–0.23)</td><td>0.02</td></tr><tr><td>Rarres2</td><td>Q99969</td><td>0.19 (0.10–0.29)</td><td>0.18</td><td>0.17 (0.08–0.27)</td><td>0.96</td></tr><tr><td>CNDP1</td><td>Q96KN2</td><td>0.19 (0.11–0.28)</td><td>0.07</td><td>0.19 (0.11–0.27)</td><td>0.19</td></tr><tr><td>EpCAM</td><td>P16422</td><td>0.19 (0.10–0.28)</td><td>0.17</td><td>0.20 (0.10–0.29)</td><td>0.29</td></tr><tr><td>CCL27</td><td>Q9Y4X3</td><td>0.19 (0.09–0.29)</td><td>0.61</td><td>0.17 (0.07–0.27)</td><td>2.16</td></tr><tr><td>SRCR</td><td>Q8WTU2</td><td>0.18 (0.09–0.27)</td><td>0.21</td><td>0.18 (0.09–0.27)</td><td>0.48</td></tr><tr><td>PLA2</td><td>P14555</td><td>0.18 (0.08–0.27)</td><td>0.54</td><td>0.16 (0.07–0.26)</td><td>2.07</td></tr><tr><td>Promotilin</td><td>P12872</td><td>0.18 (0.09–0.26)</td><td>0.26</td><td>0.16 (0.08–0.25)</td><td>1.02</td></tr><tr><td>ANGPTL4</td><td>Q9BY76</td><td>0.17 (0.11–0.23)</td><td>0.00</td><td>0.16 (0.09–0.22)</td><td>0.01</td></tr><tr><td>RBP2</td><td>P50120</td><td>0.17 (0.07–0.26)</td><td>0.98</td><td>0.15 (0.05–0.24)</td><td>4.02</td></tr><tr><td>Uromodulin</td><td>P07911</td><td>0.16 (0.10–0.22)</td><td><0.0001</td><td>0.18 (0.12–0.23)</td><td><0.0001</td></tr><tr><td>Cystatin-F</td><td>O76096</td><td>0.16 (0.07–0.25)</td><td>0.63</td><td>0.15 (0.06–0.24)</td><td>1.89</td></tr><tr><td>CCN5</td><td>O76076</td><td>0.15 (0.08–0.22)</td><td>0.14</td><td>0.14 (0.07–0.21)</td><td>0.69</td></tr><tr><td>CCL16</td><td>O15467</td><td>0.15 (0.08–0.22)</td><td>0.19</td><td>0.13 (0.06–0.21)</td><td>1.02</td></tr><tr><td>Osteopontin</td><td>P10451</td><td>0.14 (0.08–0.21)</td><td>0.18</td><td>0.13 (0.06–0.20)</td><td>1.02</td></tr><tr><td>ANGPTL2</td><td>Q9UKU9</td><td>0.14 (0.07–0.22)</td><td>0.54</td><td>0.14 (0.06–0.21)</td><td>1.16</td></tr><tr><td>NPDC1</td><td>Q9NQX5</td><td>0.14 (0.08–0.21)</td><td>0.07</td><td>0.11 (0.06–0.17)</td><td>1.02</td></tr><tr><td>Elafin</td><td>P19957</td><td>0.14 (0.07–0.21)</td><td>0.44</td><td>0.11 (0.04–0.18)</td><td>3.96</td></tr><tr><td>Cystatin-M</td><td>Q15828</td><td>0.14 (0.08–0.20)</td><td>0.10</td><td>0.11 (0.05–0.17)</td><td>1.02</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-tblfn1"></span><div content-id="tblfn1" class="footnote"><span class="fn"><p class="chapter-para">IGFBP1, insulin-like growth factor-binding protein 1; TfR1, transferrin receptor protein 1; CA2, carbonic anhydrase 2; EPO, erythropoietin; TGM2, protein-glutamine gamma-glutamyltransferase 2; TMSB10, thymosin beta-10; uMtCK, creatine kinase U-type, mitochondrial; IGFBP4, insulin-like growth factor-binding protein 4; AFABP, adipocyte fatty acid-binding protein 4; CCL18, C–C motif chemokine 18; SPINK1, serine protease inhibitor Kazal-type 1; Rarres2, retinoic acid receptor responder protein 2; CNDP1, beta-Ala-His dipeptidase; EpCAM, epithelial cell adhesion molecule; CCL27, C–C motif chemokine 27; SRCR, scavenger receptor cysteine-rich domain-containing group B protein; PLA2, phospholipase A2; ANGPTL4, angiopoietin-related protein 4; RBP2, retinol-binding protein 2; CCN5, CCN family member 5; CCL16, C–C motif chemokine 16; NPDC1, neural proliferation differentiation and control protein 1; ANGPTL2, angiopoietin-related protein 2.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="ehac495-T1" data-id="ehac495-T1"><span class="label title-label" id="label-96664">Table 1</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/388939873" aria-describedby="label-96664"> Open in new tab </a></div><div class="caption caption-id-" id="caption-96664"><p class="chapter-para">Differential expressed proteins (empagliflozin vs. placebo) at Week 12</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-96664" aria-describedby="
 caption-96664"><thead><tr><th rowspan="2">Protein<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">UniprotID<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="2">Before adjustment for change in eGFR<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="2">After adjustment for change in eGFR<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Empagliflozin vs. placebo, log<sub>2</sub> fold change (95% CI)<span aria-hidden="true" style="display: none;"> . </span></th><th>False discovery rate (%)<span aria-hidden="true" style="display: none;"> . </span></th><th>Empagliflozin vs. placebo, log<sub>2</sub> fold change (95% CI)<span aria-hidden="true" style="display: none;"> . </span></th><th>False discovery rate (%)<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>IGFBP1</td><td>P08833</td><td>0.27 (0.14–0.40)</td><td>0.16</td><td>0.25 (0.13–0.38)</td><td>0.55</td></tr><tr><td>TfR1</td><td>P02786</td><td>0.26 (0.19–0.32)</td><td><0.0001</td><td>0.25 (0.18–0.32)</td><td><0.001</td></tr><tr><td>CA2</td><td>P00918</td><td>0.25 (0.11–0.39)</td><td>0.81</td><td>0.26 (0.12–0.40)</td><td>1.02</td></tr><tr><td>EPO</td><td>P01588</td><td>0.25 (0.11–0.38)</td><td>0.65</td><td>0.24 (0.10–0.37)</td><td>1.53</td></tr><tr><td>TGM2</td><td>P21980</td><td>0.25 (0.11–0.38)</td><td>0.60</td><td>0.25 (0.12–0.38)</td><td>1.02</td></tr><tr><td>TMSB10</td><td>P63313</td><td>0.22 (0.11–0.34)</td><td>0.43</td><td>0.19 (0.08–0.31)</td><td>2.18</td></tr><tr><td>uMtCK</td><td>P12532</td><td>0.21 (0.10–0.32)</td><td>0.43</td><td>0.22 (0.11–0.33)</td><td>0.69</td></tr><tr><td>IGFBP4</td><td>P22692</td><td>0.21 (0.13–0.30)</td><td>0.01</td><td>0.17 (0.09–0.25)</td><td>0.31</td></tr><tr><td>AFABP4</td><td>P15090</td><td>0.21 (0.12–0.29)</td><td>0.02</td><td>0.17 (0.09–0.25)</td><td>0.31</td></tr><tr><td>CCL18</td><td>P55774</td><td>0.20 (0.11–0.29)</td><td>0.08</td><td>0.19 (0.10–0.28)</td><td>0.31</td></tr><tr><td>Follistatin</td><td>P19883</td><td>0.20 (0.13–0.26)</td><td><0.0001</td><td>0.19 (0.12–0.26)</td><td><0.0001</td></tr><tr><td>Midkine</td><td>P21741</td><td>0.20 (0.11–0.29)</td><td>0.14</td><td>0.18 (0.09–0.27)</td><td>0.55</td></tr><tr><td>Guanylin</td><td>Q02747</td><td>0.20 (0.13–0.26)</td><td><0.0001</td><td>0.17 (0.11–0.23)</td><td><0.001</td></tr><tr><td>SPINK1</td><td>P00995</td><td>0.20 (0.13–0.26)</td><td><0.01</td><td>0.16 (0.10–0.23)</td><td>0.02</td></tr><tr><td>Rarres2</td><td>Q99969</td><td>0.19 (0.10–0.29)</td><td>0.18</td><td>0.17 (0.08–0.27)</td><td>0.96</td></tr><tr><td>CNDP1</td><td>Q96KN2</td><td>0.19 (0.11–0.28)</td><td>0.07</td><td>0.19 (0.11–0.27)</td><td>0.19</td></tr><tr><td>EpCAM</td><td>P16422</td><td>0.19 (0.10–0.28)</td><td>0.17</td><td>0.20 (0.10–0.29)</td><td>0.29</td></tr><tr><td>CCL27</td><td>Q9Y4X3</td><td>0.19 (0.09–0.29)</td><td>0.61</td><td>0.17 (0.07–0.27)</td><td>2.16</td></tr><tr><td>SRCR</td><td>Q8WTU2</td><td>0.18 (0.09–0.27)</td><td>0.21</td><td>0.18 (0.09–0.27)</td><td>0.48</td></tr><tr><td>PLA2</td><td>P14555</td><td>0.18 (0.08–0.27)</td><td>0.54</td><td>0.16 (0.07–0.26)</td><td>2.07</td></tr><tr><td>Promotilin</td><td>P12872</td><td>0.18 (0.09–0.26)</td><td>0.26</td><td>0.16 (0.08–0.25)</td><td>1.02</td></tr><tr><td>ANGPTL4</td><td>Q9BY76</td><td>0.17 (0.11–0.23)</td><td>0.00</td><td>0.16 (0.09–0.22)</td><td>0.01</td></tr><tr><td>RBP2</td><td>P50120</td><td>0.17 (0.07–0.26)</td><td>0.98</td><td>0.15 (0.05–0.24)</td><td>4.02</td></tr><tr><td>Uromodulin</td><td>P07911</td><td>0.16 (0.10–0.22)</td><td><0.0001</td><td>0.18 (0.12–0.23)</td><td><0.0001</td></tr><tr><td>Cystatin-F</td><td>O76096</td><td>0.16 (0.07–0.25)</td><td>0.63</td><td>0.15 (0.06–0.24)</td><td>1.89</td></tr><tr><td>CCN5</td><td>O76076</td><td>0.15 (0.08–0.22)</td><td>0.14</td><td>0.14 (0.07–0.21)</td><td>0.69</td></tr><tr><td>CCL16</td><td>O15467</td><td>0.15 (0.08–0.22)</td><td>0.19</td><td>0.13 (0.06–0.21)</td><td>1.02</td></tr><tr><td>Osteopontin</td><td>P10451</td><td>0.14 (0.08–0.21)</td><td>0.18</td><td>0.13 (0.06–0.20)</td><td>1.02</td></tr><tr><td>ANGPTL2</td><td>Q9UKU9</td><td>0.14 (0.07–0.22)</td><td>0.54</td><td>0.14 (0.06–0.21)</td><td>1.16</td></tr><tr><td>NPDC1</td><td>Q9NQX5</td><td>0.14 (0.08–0.21)</td><td>0.07</td><td>0.11 (0.06–0.17)</td><td>1.02</td></tr><tr><td>Elafin</td><td>P19957</td><td>0.14 (0.07–0.21)</td><td>0.44</td><td>0.11 (0.04–0.18)</td><td>3.96</td></tr><tr><td>Cystatin-M</td><td>Q15828</td><td>0.14 (0.08–0.20)</td><td>0.10</td><td>0.11 (0.05–0.17)</td><td>1.02</td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th rowspan="2">Protein<span aria-hidden="true" style="display: none;"> . </span></th><th rowspan="2">UniprotID<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="2">Before adjustment for change in eGFR<span aria-hidden="true" style="display: none;"> . </span></th><th colspan="2">After adjustment for change in eGFR<span aria-hidden="true" style="display: none;"> . </span></th></tr><tr><th>Empagliflozin vs. placebo, log<sub>2</sub> fold change (95% CI)<span aria-hidden="true" style="display: none;"> . </span></th><th>False discovery rate (%)<span aria-hidden="true" style="display: none;"> . </span></th><th>Empagliflozin vs. placebo, log<sub>2</sub> fold change (95% CI)<span aria-hidden="true" style="display: none;"> . </span></th><th>False discovery rate (%)<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td>IGFBP1</td><td>P08833</td><td>0.27 (0.14–0.40)</td><td>0.16</td><td>0.25 (0.13–0.38)</td><td>0.55</td></tr><tr><td>TfR1</td><td>P02786</td><td>0.26 (0.19–0.32)</td><td><0.0001</td><td>0.25 (0.18–0.32)</td><td><0.001</td></tr><tr><td>CA2</td><td>P00918</td><td>0.25 (0.11–0.39)</td><td>0.81</td><td>0.26 (0.12–0.40)</td><td>1.02</td></tr><tr><td>EPO</td><td>P01588</td><td>0.25 (0.11–0.38)</td><td>0.65</td><td>0.24 (0.10–0.37)</td><td>1.53</td></tr><tr><td>TGM2</td><td>P21980</td><td>0.25 (0.11–0.38)</td><td>0.60</td><td>0.25 (0.12–0.38)</td><td>1.02</td></tr><tr><td>TMSB10</td><td>P63313</td><td>0.22 (0.11–0.34)</td><td>0.43</td><td>0.19 (0.08–0.31)</td><td>2.18</td></tr><tr><td>uMtCK</td><td>P12532</td><td>0.21 (0.10–0.32)</td><td>0.43</td><td>0.22 (0.11–0.33)</td><td>0.69</td></tr><tr><td>IGFBP4</td><td>P22692</td><td>0.21 (0.13–0.30)</td><td>0.01</td><td>0.17 (0.09–0.25)</td><td>0.31</td></tr><tr><td>AFABP4</td><td>P15090</td><td>0.21 (0.12–0.29)</td><td>0.02</td><td>0.17 (0.09–0.25)</td><td>0.31</td></tr><tr><td>CCL18</td><td>P55774</td><td>0.20 (0.11–0.29)</td><td>0.08</td><td>0.19 (0.10–0.28)</td><td>0.31</td></tr><tr><td>Follistatin</td><td>P19883</td><td>0.20 (0.13–0.26)</td><td><0.0001</td><td>0.19 (0.12–0.26)</td><td><0.0001</td></tr><tr><td>Midkine</td><td>P21741</td><td>0.20 (0.11–0.29)</td><td>0.14</td><td>0.18 (0.09–0.27)</td><td>0.55</td></tr><tr><td>Guanylin</td><td>Q02747</td><td>0.20 (0.13–0.26)</td><td><0.0001</td><td>0.17 (0.11–0.23)</td><td><0.001</td></tr><tr><td>SPINK1</td><td>P00995</td><td>0.20 (0.13–0.26)</td><td><0.01</td><td>0.16 (0.10–0.23)</td><td>0.02</td></tr><tr><td>Rarres2</td><td>Q99969</td><td>0.19 (0.10–0.29)</td><td>0.18</td><td>0.17 (0.08–0.27)</td><td>0.96</td></tr><tr><td>CNDP1</td><td>Q96KN2</td><td>0.19 (0.11–0.28)</td><td>0.07</td><td>0.19 (0.11–0.27)</td><td>0.19</td></tr><tr><td>EpCAM</td><td>P16422</td><td>0.19 (0.10–0.28)</td><td>0.17</td><td>0.20 (0.10–0.29)</td><td>0.29</td></tr><tr><td>CCL27</td><td>Q9Y4X3</td><td>0.19 (0.09–0.29)</td><td>0.61</td><td>0.17 (0.07–0.27)</td><td>2.16</td></tr><tr><td>SRCR</td><td>Q8WTU2</td><td>0.18 (0.09–0.27)</td><td>0.21</td><td>0.18 (0.09–0.27)</td><td>0.48</td></tr><tr><td>PLA2</td><td>P14555</td><td>0.18 (0.08–0.27)</td><td>0.54</td><td>0.16 (0.07–0.26)</td><td>2.07</td></tr><tr><td>Promotilin</td><td>P12872</td><td>0.18 (0.09–0.26)</td><td>0.26</td><td>0.16 (0.08–0.25)</td><td>1.02</td></tr><tr><td>ANGPTL4</td><td>Q9BY76</td><td>0.17 (0.11–0.23)</td><td>0.00</td><td>0.16 (0.09–0.22)</td><td>0.01</td></tr><tr><td>RBP2</td><td>P50120</td><td>0.17 (0.07–0.26)</td><td>0.98</td><td>0.15 (0.05–0.24)</td><td>4.02</td></tr><tr><td>Uromodulin</td><td>P07911</td><td>0.16 (0.10–0.22)</td><td><0.0001</td><td>0.18 (0.12–0.23)</td><td><0.0001</td></tr><tr><td>Cystatin-F</td><td>O76096</td><td>0.16 (0.07–0.25)</td><td>0.63</td><td>0.15 (0.06–0.24)</td><td>1.89</td></tr><tr><td>CCN5</td><td>O76076</td><td>0.15 (0.08–0.22)</td><td>0.14</td><td>0.14 (0.07–0.21)</td><td>0.69</td></tr><tr><td>CCL16</td><td>O15467</td><td>0.15 (0.08–0.22)</td><td>0.19</td><td>0.13 (0.06–0.21)</td><td>1.02</td></tr><tr><td>Osteopontin</td><td>P10451</td><td>0.14 (0.08–0.21)</td><td>0.18</td><td>0.13 (0.06–0.20)</td><td>1.02</td></tr><tr><td>ANGPTL2</td><td>Q9UKU9</td><td>0.14 (0.07–0.22)</td><td>0.54</td><td>0.14 (0.06–0.21)</td><td>1.16</td></tr><tr><td>NPDC1</td><td>Q9NQX5</td><td>0.14 (0.08–0.21)</td><td>0.07</td><td>0.11 (0.06–0.17)</td><td>1.02</td></tr><tr><td>Elafin</td><td>P19957</td><td>0.14 (0.07–0.21)</td><td>0.44</td><td>0.11 (0.04–0.18)</td><td>3.96</td></tr><tr><td>Cystatin-M</td><td>Q15828</td><td>0.14 (0.08–0.20)</td><td>0.10</td><td>0.11 (0.05–0.17)</td><td>1.02</td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-tblfn1"></span><div content-id="tblfn1" class="footnote"><span class="fn"><p class="chapter-para">IGFBP1, insulin-like growth factor-binding protein 1; TfR1, transferrin receptor protein 1; CA2, carbonic anhydrase 2; EPO, erythropoietin; TGM2, protein-glutamine gamma-glutamyltransferase 2; TMSB10, thymosin beta-10; uMtCK, creatine kinase U-type, mitochondrial; IGFBP4, insulin-like growth factor-binding protein 4; AFABP, adipocyte fatty acid-binding protein 4; CCL18, C–C motif chemokine 18; SPINK1, serine protease inhibitor Kazal-type 1; Rarres2, retinoic acid receptor responder protein 2; CNDP1, beta-Ala-His dipeptidase; EpCAM, epithelial cell adhesion molecule; CCL27, C–C motif chemokine 27; SRCR, scavenger receptor cysteine-rich domain-containing group B protein; PLA2, phospholipase A2; ANGPTL4, angiopoietin-related protein 4; RBP2, retinol-binding protein 2; CCN5, CCN family member 5; CCL16, C–C motif chemokine 16; NPDC1, neural proliferation differentiation and control protein 1; ANGPTL2, angiopoietin-related protein 2.</p></span></div></div></div></div><p class="chapter-para">Among these, nine proteins demonstrated the largest treatment effect of empagliflozin (log<sub>2</sub> fold change >0.201, corresponding to a >15% increase) with a false discovery rate of <1%. These were insulin-like growth factor-binding protein 1 (IGFBP1), transferrin receptor protein 1 (TfR1), carbonic anhydrase 2 (CA2), erythropoietin (EPO), protein-glutamine gamma-glutamyltransferase 2 (TGM2), thymosin beta-10 (TMSB10), mitochondrial creatine kinase U-type (uMtCK), insulin-like growth factor-binding protein 4 (IGFBP4), and adipocyte fatty acid-binding protein 4 (AFABP4). Among these, the effect of empagliflozin on TfR1 was particularly noteworthy with a nearly 20% increase and an exceptionally low false discovery rate (2.5 × 10<sup>−10</sup>) with a raw <em>P</em>-value of 1.9 × 10<sup>−13</sup>.</p><p class="chapter-para">The effects of empagliflozin (corrected for placebo) on all measured circulating proteins (corrected for placebo) from the baseline to Week 12 are shown in <span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Supplementary material online</a></span>, <em><span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Table S2</a></span></em> and displayed in <span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Supplementary material online</a></span>, <em><span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Figure S1</a></span></em>. No differentially expressed protein showed a statistically significant interaction between EMPEROR-Reduced and EMPEROR-Preserved at Week 12, <span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Supplementary material online</a></span>, <em><span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Table S3</a></span></em>. No differentially expressed protein met the criteria for a meaningful decrease in level at Week 12. Of note, <em>N</em>-terminal prohormone B-type natriuretic peptide declined at 12 weeks, but the change was not statistically significant.</p><p class="chapter-para">In a <em>post hoc</em> sensitivity analysis, we examined the effects of empagliflozin vs. placebo on the changes in protein levels from the baseline for all 1283 proteins after the inclusion of the change in eGFR from baseline to Week 12 as an additional covariate. No new proteins were found to be differentially expressed. Of the 32 differentially expressed proteins in our original model, adjustment for the change in eGFR did not meaningfully influence the effect size for proteins with the largest treatment effect, but five of the six proteins with the smallest changes in our original model now fell meaningfully below the threshold of log<sub>2</sub> fold change of 0.1375 following adjustment (<em><span class="xrefLink" id="jumplink-ehac495-T1"></span><a href="javascript:;" reveal-id="ehac495-T1" data-open="ehac495-T1" class="link link-reveal link-table xref-fig">Table 1</a></em>). For the remaining 27 proteins, the false discovery rate generally increased modestly, but remained <5% for all proteins, and was <2% for all but 4 proteins.</p> <h3 scrollto-destination=388939877 id="388939877" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s2.3>Differentially expressed proteins at Week 52</h3> <p class="chapter-para">The changes of the proteins from baseline to Week 52 were generally concordant with the changes from baseline to Week 12 (see <span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Supplementary material online</a></span>, <em><span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Figure S1</a></span></em>), as demonstrated by a lack of significant treatment-by-time interactions for all proteins, with one exception. When compared with placebo, empagliflozin did not have a meaningful effect on kidney injury molecule-1 (KIM-1) at Week 12, but it decreased KIM-1 at Week 52 (<em><span class="xrefLink" id="jumplink-ehac495-F1"></span><a href="javascript:;" data-modal-source-id="ehac495-F1" class="link xref-fig">Figure 1</a></em>), log<sub>2</sub> fold change −0.18 (95% CI −0.10 to −0.27), a 12% decrease with a false discovery rate of 0.006%. The effect of empagliflozin on KIM-1 at 52 weeks was significantly different from that at 12 weeks, visit-by-treatment interaction false discovery rate of 0.008%.</p> <a id="388939879" scrollto-destination="388939879"></a> <div data-id="ehac495-f1" data-content-id="ehac495-f1" class="fig fig-section js-fig-section" swap-content-for-modal="true"><div class="graphic-wrap"><img class="content-image" src="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/m_ehac495f1.jpeg?Expires=1735388495&Signature=iNaKoi73MloJTaH6oA~r3miQdED6yLX2~90bw8sx5iQwAjoDPzSXBFDDpU69oc9GB0pSruim4qMhY7uCtL~bx2IpWqk5zGlhbotdAOiRSz71WUnkf6XyiITTAr40xeKy6f-W0rErkiBqLey-eSQWMZDSGRvxrHU7CviJPWAbzK0Jn6bZj109YbqiH1LGfYmt0qQu1TpLAKe7cSuSrmN9ozjmcFFR6tlQkntAlEBPmPXFag2dK9ZuS0JRosXpeCWuGndVEu8J3gKMu7qm-506AfgKz4ne1-LzdiEFX3lMQBEPsU70ZpBRZ5oUMpiAv38JmMjDON2P9q1B7L7~frYdhw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA" alt="Kidney injury molecule-1 (KIM-1). Changes from baseline in the empagliflozin and placebo groups at Week 12 and Week 52." data-path-from-xml="ehac495f1.tif" /><div class="graphic-bottom"><div class="label fig-label" id="label-388939879">Figure 1</div><div class="caption fig-caption"><p class="chapter-para">Kidney injury molecule-1 (KIM-1). Changes from baseline in the empagliflozin and placebo groups at Week 12 and Week 52.</p></div><div class="ajax-articleAbstract-exclude-regex fig-orig original-slide figure-button-wrap"><a class="fig-view-orig js-view-large at-figureViewLarge openInAnotherWindow" role="button" aria-describedby="label-388939879" href="/view-large/figure/388939879/ehac495f1.tif" data-path-from-xml="ehac495f1.tif" target="_blank">Open in new tab</a><a class="download-slide" role="button" aria-describedby="label-388939879" data-section="388939879" href="/DownloadFile/DownloadImage.aspx?image=https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495f1.jpeg?Expires=1735388495&Signature=XwSJEStt2Ahe-0TURe9Dftx85LqDodI0oLY8uSSXLzJtcPRkm8wOG1zL3tR4lCZjsHENZK8eI5pbq-CHyn74zeTtysy78GXcHHcSi7Y-egM9U2fTiEk9ODppUGDy~Fa-q2Iwa089-Q6zIkL0~xFW1EzGTsO-VStBRi9idnKIH1hRuh4NYz6yh2WDiX82pZcfV0ENCgESRE04bL7YlE8VhZ9QviKQuT6lBORjwM-oZglKnRicbsLrTvwjhFz7LOc~nwj6pfQT6kxXpmNot9cE6UhCgWwCsDBULRNTpT4kSHU5WX1XDT02nI~pio-mnWyRnGD~nLyjpxcdFG9TrerLLg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA&sec=388939879&ar=6676779&xsltPath=~/UI/app/XSLT&imagename=&siteId=5375" data-path-from-xml="ehac495f1.tif">Download slide</a></div></div></div></div> <h3 scrollto-destination=388939880 id="388939880" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s2.4>Biological actions of differential expressed proteins on the heart and kidney</h3> <p class="chapter-para">As noted above, after adjustment for changes in eGFR, the circulating levels of 27 proteins were increased by ≈10% or more by empagliflozin at 12 weeks, and one protein was decreased by at least 10% by the drug at 52 weeks. The known biological effects of these 28 proteins are shown in <em><span class="xrefLink" id="jumplink-ehac495-T2"></span><a href="javascript:;" reveal-id="ehac495-T2" data-open="ehac495-T2" class="link link-reveal link-table xref-fig">Table 2</a></em>.<sup><span class="xrefLink" id="jumplink-ehac495-B10 ehac495-B11 ehac495-B12 ehac495-B13 ehac495-B14 ehac495-B15 ehac495-B16 ehac495-B17 ehac495-B18 ehac495-B19 ehac495-B20 ehac495-B21 ehac495-B22 ehac495-B23 ehac495-B24 ehac495-B25 ehac495-B26 ehac495-B27 ehac495-B28 ehac495-B29 ehac495-B30 ehac495-B31 ehac495-B32 ehac495-B33 ehac495-B34 ehac495-B35 ehac495-B36 ehac495-B37 ehac495-B38 ehac495-B39 ehac495-B40 ehac495-B41 ehac495-B42 ehac495-B43 ehac495-B44 ehac495-B45 ehac495-B46 ehac495-B47 ehac495-B48 ehac495-B49 ehac495-B50 ehac495-B51 ehac495-B52 ehac495-B53 ehac495-B54 ehac495-B55 ehac495-B56 ehac495-B57 ehac495-B58 ehac495-B59 ehac495-B60 ehac495-B61 ehac495-B62"></span><a href="javascript:;" reveal-id="ehac495-B10 ehac495-B11 ehac495-B12 ehac495-B13 ehac495-B14 ehac495-B15 ehac495-B16 ehac495-B17 ehac495-B18 ehac495-B19 ehac495-B20 ehac495-B21 ehac495-B22 ehac495-B23 ehac495-B24 ehac495-B25 ehac495-B26 ehac495-B27 ehac495-B28 ehac495-B29 ehac495-B30 ehac495-B31 ehac495-B32 ehac495-B33 ehac495-B34 ehac495-B35 ehac495-B36 ehac495-B37 ehac495-B38 ehac495-B39 ehac495-B40 ehac495-B41 ehac495-B42 ehac495-B43 ehac495-B44 ehac495-B45 ehac495-B46 ehac495-B47 ehac495-B48 ehac495-B49 ehac495-B50 ehac495-B51 ehac495-B52 ehac495-B53 ehac495-B54 ehac495-B55 ehac495-B56 ehac495-B57 ehac495-B58 ehac495-B59 ehac495-B60 ehac495-B61 ehac495-B62" data-open="ehac495-B10 ehac495-B11 ehac495-B12 ehac495-B13 ehac495-B14 ehac495-B15 ehac495-B16 ehac495-B17 ehac495-B18 ehac495-B19 ehac495-B20 ehac495-B21 ehac495-B22 ehac495-B23 ehac495-B24 ehac495-B25 ehac495-B26 ehac495-B27 ehac495-B28 ehac495-B29 ehac495-B30 ehac495-B31 ehac495-B32 ehac495-B33 ehac495-B34 ehac495-B35 ehac495-B36 ehac495-B37 ehac495-B38 ehac495-B39 ehac495-B40 ehac495-B41 ehac495-B42 ehac495-B43 ehac495-B44 ehac495-B45 ehac495-B46 ehac495-B47 ehac495-B48 ehac495-B49 ehac495-B50 ehac495-B51 ehac495-B52 ehac495-B53 ehac495-B54 ehac495-B55 ehac495-B56 ehac495-B57 ehac495-B58 ehac495-B59 ehac495-B60 ehac495-B61 ehac495-B62" class="link link-ref link-reveal xref-bibr">10–62</a></sup></p> <a id="388939882" scrollto-destination="388939882"></a> <div content-id="ehac495-T2" class="table-modal table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="ehac495-T2" data-id="ehac495-T2"><span class="label title-label" id="label-32545">Table 2</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/388939882" aria-describedby="label-32545"> Open in new tab </a></div><div class="caption caption-id-" id="caption-32545"><p class="chapter-para">Biological effect of differentially expressed proteins on heart and kidney</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-32545" aria-describedby="
 caption-32545"><thead><tr><th>Protein<span aria-hidden="true" style="display: none;"> . </span></th><th>Cellular action<span aria-hidden="true" style="display: none;"> . </span></th><th>Effects on heart, kidney, and other Sites<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="3"><span class="sans-serif"><strong>Proteins with effects on the heart</strong></span></td></tr><tr><td><span class="sans-serif">Insulin-like growth factor-binding protein 1 (IGFBP1)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy</span></td><td><span class="sans-serif">IGF1 promotes heart failure by inhibiting cardiac autophagy; increases in IGFBP1 interfere with actions of IGF1, thus promoting autophagy.</span><sup><span class="xrefLink" id="jumplink-ehac495-B10"></span><a href="javascript:;" reveal-id="ehac495-B10" data-open="ehac495-B10" class="link link-ref link-reveal xref-bibr">10</a></sup><span class="sans-serif">IGFBP1 also promotes HIF-1</span>α <span class="sans-serif">stability and inhibits cardiomyocyte apoptosis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B11"></span><a href="javascript:;" reveal-id="ehac495-B11" data-open="ehac495-B11" class="link link-ref link-reveal xref-bibr">11</a></sup><span class="sans-serif">Expression of IGFBP1 is upregulated by sirtuin-1.</span><sup><span class="xrefLink" id="jumplink-ehac495-B12"></span><a href="javascript:;" reveal-id="ehac495-B12" data-open="ehac495-B12" class="link link-ref link-reveal xref-bibr">12</a></sup></td></tr><tr><td><span class="sans-serif">Transferrin receptor protein 1 (TfRI)</span></td><td><span class="sans-serif">Promotion of cardiac iron metabolism and cardiac autophagy; improved mitochondrial health</span></td><td><span class="sans-serif">Required for iron transport into cardiomyocytes. TfR1 knockout leads to mitochondrial dysfunction, down-regulation of cardiac autophagy proteins and cardiomyopathy, which can be prevented by sirtuin-1 activation.</span><sup><span class="xrefLink" id="jumplink-ehac495-B13"></span><a href="javascript:;" reveal-id="ehac495-B13" data-open="ehac495-B13" class="link link-ref link-reveal xref-bibr">13</a></sup><span class="sans-serif">TfR1-mediated changes in transmembrane electron transport provides NAD + required for sirtuin activation.</span><sup><span class="xrefLink" id="jumplink-ehac495-B14"></span><a href="javascript:;" reveal-id="ehac495-B14" data-open="ehac495-B14" class="link link-ref link-reveal xref-bibr">14</a></sup></td></tr><tr><td><span class="sans-serif">Erythropoietin (EPO)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy and inhibition of cardiac fibrosis</span></td><td><span class="sans-serif">Prevents cardiac remodelling, resulting from promotion of autophagy and mitigates apoptosis and inflammation and fibrosis in the heart.</span><sup><span class="xrefLink" id="jumplink-ehac495-B15 ehac495-B16 ehac495-B17"></span><a href="javascript:;" reveal-id="ehac495-B15 ehac495-B16 ehac495-B17" data-open="ehac495-B15 ehac495-B16 ehac495-B17" class="link link-ref link-reveal xref-bibr">15–17</a></sup><span class="sans-serif">Expression and actions are AMPK- and sirtuin-dependent.</span><sup><span class="xrefLink" id="jumplink-ehac495-B15"></span><a href="javascript:;" reveal-id="ehac495-B15" data-open="ehac495-B15" class="link link-ref link-reveal xref-bibr">15</a>,<span class="xrefLink" id="jumplink-ehac495-B17"></span><a href="javascript:;" reveal-id="ehac495-B17" data-open="ehac495-B17" class="link link-ref link-reveal xref-bibr">17</a>,<span class="xrefLink" id="jumplink-ehac495-B18"></span><a href="javascript:;" reveal-id="ehac495-B18" data-open="ehac495-B18" class="link link-ref link-reveal xref-bibr">18</a></sup></td></tr><tr><td><span class="sans-serif">Follistatin (FST)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy</span></td><td><span class="sans-serif">Follistatin and follistatin-like proteins interact with the same receptors. Follistatin-like protein 1 reduces myocardial injury, apoptosis, remodelling, hypertrophy, and fibrosis by promoting autophagy through effects on AMPK.</span><sup><span class="xrefLink" id="jumplink-ehac495-B19"></span><a href="javascript:;" reveal-id="ehac495-B19" data-open="ehac495-B19" class="link link-ref link-reveal xref-bibr">19</a>,<span class="xrefLink" id="jumplink-ehac495-B20"></span><a href="javascript:;" reveal-id="ehac495-B20" data-open="ehac495-B20" class="link link-ref link-reveal xref-bibr">20</a></sup></td></tr><tr><td><span class="sans-serif">Retinol-binding protein 2 (RBP2)</span></td><td><span class="sans-serif">Promotion of renal autophagy; inhibition of cardiac apoptosis and enhanced cardiac regenerative capacity</span></td><td><span class="sans-serif">Retinoic acid levels decline in heart failure. Facilitates dietary retinol uptake, thereby mitigating cardiomyocyte apoptosis and promoting cardiac regenerative capacity.</span><sup>21–23</sup><span class="sans-serif">Prevents renal injury by promoting autophagy in the kidney.</span><sup><span class="xrefLink" id="jumplink-ehac495-B24"></span><a href="javascript:;" reveal-id="ehac495-B24" data-open="ehac495-B24" class="link link-ref link-reveal xref-bibr">24</a></sup></td></tr><tr><td><span class="sans-serif">Midkine (Mdk)</span></td><td><span class="sans-serif">Inhibition of cardiac apoptosis</span></td><td><span class="sans-serif">Reduces cardiac injury, mitigation of cardiac apoptosis and remodelling; promotes angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B25"></span><a href="javascript:;" reveal-id="ehac495-B25" data-open="ehac495-B25" class="link link-ref link-reveal xref-bibr">25</a>,<span class="xrefLink" id="jumplink-ehac495-B26"></span><a href="javascript:;" reveal-id="ehac495-B26" data-open="ehac495-B26" class="link link-ref link-reveal xref-bibr">26</a></sup></td></tr><tr><td><span class="sans-serif">Phospholipase A2, membrane-associated (PLA2)</span></td><td><span class="sans-serif">Promotion of cardiac repair following oxidative stress</span></td><td><span class="sans-serif">Calcium-independent PLA2 in ventricular cardiomyocytes localizes to mitochondria and peroxisomes and acts as a phospholipid repair enzyme following oxidative damage. Inhibition of phospholipase A2 is a mechanism underlying anthracycline cardiotoxicity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B27"></span><a href="javascript:;" reveal-id="ehac495-B27" data-open="ehac495-B27" class="link link-ref link-reveal xref-bibr">27</a>,<span class="xrefLink" id="jumplink-ehac495-B28"></span><a href="javascript:;" reveal-id="ehac495-B28" data-open="ehac495-B28" class="link link-ref link-reveal xref-bibr">28</a></sup></td></tr><tr><td><span class="sans-serif">Angiopoietin-related protein 4 (ANGPTL4)</span></td><td><span class="sans-serif">Reduction of oxidative stress and promotion of endothelial cell autophagy</span></td><td><span class="sans-serif">Inhibits lipoprotein lipase in cardiomyocytes. Prevents fatty acid-induced oxidative stress.</span><sup><span class="xrefLink" id="jumplink-ehac495-B29"></span><a href="javascript:;" reveal-id="ehac495-B29" data-open="ehac495-B29" class="link link-ref link-reveal xref-bibr">29</a></sup><span class="sans-serif">Preserves endothelial integrity by promotion of autophagy, thereby supporting myocardial function.</span><sup><span class="xrefLink" id="jumplink-ehac495-B30"></span><a href="javascript:;" reveal-id="ehac495-B30" data-open="ehac495-B30" class="link link-ref link-reveal xref-bibr">30</a></sup></td></tr><tr><td><span class="sans-serif">Insulin-like growth factor-binding protein 4 (IGFBP4)</span></td><td><span class="sans-serif">Reduction of oxidative stress and promotion of cardiac regenerative capacity</span></td><td><span class="sans-serif">Produces cardioprotection by minimizing the DNA injury produced by oxidative stress and promotes angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B31"></span><a href="javascript:;" reveal-id="ehac495-B31" data-open="ehac495-B31" class="link link-ref link-reveal xref-bibr">31</a></sup><span class="sans-serif">Enhances induction of cardiomyocytes from pluripotential stem cells by inhibition of the Wnt/β-catenin signalling, independent of its binding to IGF.</span><sup><span class="xrefLink" id="jumplink-ehac495-B32"></span><a href="javascript:;" reveal-id="ehac495-B32" data-open="ehac495-B32" class="link link-ref link-reveal xref-bibr">32</a></sup></td></tr><tr><td><span class="sans-serif">Protein-glutamine gamma-glutamyltransferase 2 (TGM2)</span></td><td><span class="sans-serif">Enhanced cardiac ATP synthesis, cardiac repair and regenerative capacity</span></td><td><span class="sans-serif">Enhanced fatty acid utilization and ATP synthesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B33"></span><a href="javascript:;" reveal-id="ehac495-B33" data-open="ehac495-B33" class="link link-ref link-reveal xref-bibr">33</a></sup><span class="sans-serif">Promotes cardiac repair and regenerative capacity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B34"></span><a href="javascript:;" reveal-id="ehac495-B34" data-open="ehac495-B34" class="link link-ref link-reveal xref-bibr">34</a></sup></td></tr><tr><td><span class="sans-serif">Mitochondrial creatine kinase, U-type (uMtCK)</span></td><td><span class="sans-serif">Support of cardiac energy metabolism</span></td><td><span class="sans-serif">Mediates the transfer of high energy phosphate from mitochondria to cytosol. Compensatory increase following oxidative stress has cardioprotective effects.</span><sup><span class="xrefLink" id="jumplink-ehac495-B35 ehac495-B36 ehac495-B37"></span><a href="javascript:;" reveal-id="ehac495-B35 ehac495-B36 ehac495-B37" data-open="ehac495-B35 ehac495-B36 ehac495-B37" class="link link-ref link-reveal xref-bibr">35–37</a></sup></td></tr><tr><td><span class="sans-serif">Connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed family member 5 (CCN5)</span></td><td><span class="sans-serif">Inhibition of cardiac fibrosis</span></td><td><span class="sans-serif">Inhibits cardiac hypertrophy. Interferes with endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, thereby reducing cardiac fibrosis. Prevents structural and electrical remodelling. Knockout leads to cardiomyopathy.</span><sup><span class="xrefLink" id="jumplink-ehac495-B38"></span><a href="javascript:;" reveal-id="ehac495-B38" data-open="ehac495-B38" class="link link-ref link-reveal xref-bibr">38</a>,<span class="xrefLink" id="jumplink-ehac495-B39"></span><a href="javascript:;" reveal-id="ehac495-B39" data-open="ehac495-B39" class="link link-ref link-reveal xref-bibr">39</a></sup></td></tr><tr><td><span class="sans-serif">Adipocyte fatty acid-binding protein 4 (AFABP4)</span></td><td><span class="sans-serif">Suppression of cardiac contractility</span></td><td><span class="sans-serif">Lipid binding protein that reduces fatty acid uptake by myocardium, thus suppresses cardiac contractility.</span><sup><span class="xrefLink" id="jumplink-ehac495-B40"></span><a href="javascript:;" reveal-id="ehac495-B40" data-open="ehac495-B40" class="link link-ref link-reveal xref-bibr">40</a>,<span class="xrefLink" id="jumplink-ehac495-B41"></span><a href="javascript:;" reveal-id="ehac495-B41" data-open="ehac495-B41" class="link link-ref link-reveal xref-bibr">41</a></sup><span class="sans-serif">May act as indicator of increased sirtuin-1 signalling and autophagic flux</span>.<sup><span class="xrefLink" id="jumplink-ehac495-B42"></span><a href="javascript:;" reveal-id="ehac495-B42" data-open="ehac495-B42" class="link link-ref link-reveal xref-bibr">42</a></sup></td></tr><tr><td><span class="sans-serif">Retinoic acid receptor responder protein 2 (Rarres2, chemerin)</span></td><td><span class="sans-serif">Promotion of cardiac hypertrophy, apoptosis, and angiogenesis</span></td><td><span class="sans-serif">Adipokine that induces cardiomyocyte hypertrophy, apoptosis, and angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B43"></span><a href="javascript:;" reveal-id="ehac495-B43" data-open="ehac495-B43" class="link link-ref link-reveal xref-bibr">43</a>,<span class="xrefLink" id="jumplink-ehac495-B44"></span><a href="javascript:;" reveal-id="ehac495-B44" data-open="ehac495-B44" class="link link-ref link-reveal xref-bibr">44</a></sup><span class="sans-serif">May act as biomarker of renal function, being inversely related to glomerular filtration rate.</span><sup><span class="xrefLink" id="jumplink-ehac495-B45"></span><a href="javascript:;" reveal-id="ehac495-B45" data-open="ehac495-B45" class="link link-ref link-reveal xref-bibr">45</a></sup></td></tr><tr><td colspan="3"><span class="sans-serif"><strong>Proteins with effects on the kidneys</strong></span></td></tr><tr><td><span class="sans-serif">Carbonic anhydrase 2 (CA2)</span></td><td><span class="sans-serif">Renal tubular sodium, bicarbonate, and water homeostasis</span></td><td><span class="sans-serif">Binds to and enhances the activity of NHE3 in the proximal renal tubule.</span><sup><span class="xrefLink" id="jumplink-ehac495-B46"></span><a href="javascript:;" reveal-id="ehac495-B46" data-open="ehac495-B46" class="link link-ref link-reveal xref-bibr">46</a></sup><span class="sans-serif">May offset increases in urinary bicarbonate and water resulting from SGLT2 inhibition.</span></td></tr><tr><td><span class="sans-serif">Guanylin (GUCA)</span></td><td><span class="sans-serif">Renal tubular sodium transport</span></td><td><span class="sans-serif">After the dietary salt load, guanylin and uroguanylin promote natriuresis by inhibiting NHE3 in proximal tubule</span><sup><span class="xrefLink" id="jumplink-ehac495-B47"></span><a href="javascript:;" reveal-id="ehac495-B47" data-open="ehac495-B47" class="link link-ref link-reveal xref-bibr">47</a>,<span class="xrefLink" id="jumplink-ehac495-B48"></span><a href="javascript:;" reveal-id="ehac495-B48" data-open="ehac495-B48" class="link link-ref link-reveal xref-bibr">48</a></sup></td></tr><tr><td><span class="sans-serif">Uromodulin (UMOD)</span></td><td><span class="sans-serif">Renal tubular sodium transport and muting of renal inflammation</span></td><td><span class="sans-serif">Promotes sodium reabsorption in the thick ascending limb of the loop of Henle.</span><sup><span class="xrefLink" id="jumplink-ehac495-B49"></span><a href="javascript:;" reveal-id="ehac495-B49" data-open="ehac495-B49" class="link link-ref link-reveal xref-bibr">49</a>,<span class="xrefLink" id="jumplink-ehac495-B50"></span><a href="javascript:;" reveal-id="ehac495-B50" data-open="ehac495-B50" class="link link-ref link-reveal xref-bibr">50</a></sup><span class="sans-serif">Acts as a trap for proinflammatory renal cytokines; loss-of-function mutations lead to chronic kidney disease.</span><sup><span class="xrefLink" id="jumplink-ehac495-B51"></span><a href="javascript:;" reveal-id="ehac495-B51" data-open="ehac495-B51" class="link link-ref link-reveal xref-bibr">51</a></sup></td></tr><tr><td><span class="sans-serif">Kidney injury molecule-1 (KIM-1)</span></td><td><span class="sans-serif">Promotion of renal proximal tubular injury, inflammation, and fibrosis</span></td><td><span class="sans-serif">Mediates renal tubular cell injury and apoptosis and promotes tubulointerstitial inflammation and fibrosis</span><sup><span class="xrefLink" id="jumplink-ehac495-B52 ehac495-B53 ehac495-B54"></span><a href="javascript:;" reveal-id="ehac495-B52 ehac495-B53 ehac495-B54" data-open="ehac495-B52 ehac495-B53 ehac495-B54" class="link link-ref link-reveal xref-bibr">52–54</a></sup></td></tr><tr><td><span class="sans-serif">Epithelial cell adhesion molecule (EpCAM)</span></td><td><span class="sans-serif">Promotion of renal tubular integrity and regeneration</span></td><td><span class="sans-serif">Promotes adhesion and polarity of renal tubular cells. EpCAM is suppressed by nephrotoxic agents and is enhanced during renal tubular regeneration</span><sup><span class="xrefLink" id="jumplink-ehac495-B55"></span><a href="javascript:;" reveal-id="ehac495-B55" data-open="ehac495-B55" class="link link-ref link-reveal xref-bibr">55</a>,<span class="xrefLink" id="jumplink-ehac495-B56"></span><a href="javascript:;" reveal-id="ehac495-B56" data-open="ehac495-B56" class="link link-ref link-reveal xref-bibr">56</a></sup></td></tr><tr><td><span class="sans-serif">Thymosin beta-10 (TMSB10)</span></td><td><span class="sans-serif">Promotion of renal tubular integrity and regeneration</span></td><td><span class="sans-serif">Plays important role in organization of cytoskeleton, thus promoting adhesion and polarity of renal parenchymal cells</span><sup><span class="xrefLink" id="jumplink-ehac495-B57"></span><a href="javascript:;" reveal-id="ehac495-B57" data-open="ehac495-B57" class="link link-ref link-reveal xref-bibr">57</a>,<span class="xrefLink" id="jumplink-ehac495-B58"></span><a href="javascript:;" reveal-id="ehac495-B58" data-open="ehac495-B58" class="link link-ref link-reveal xref-bibr">58</a></sup></td></tr><tr><td><span class="sans-serif">Beta-Ala-His dipeptidase (carnosinase 1, CNDP1)</span></td><td><span class="sans-serif">Degradation of nephroprotective carnosine</span></td><td><span class="sans-serif">Carnosine protects against the development of nephropathy, and gain-of-function mutations of carnosinase-1 cause carnosine depletion and increase risk of chronic kidney disease.</span><sup><span class="xrefLink" id="jumplink-ehac495-B59"></span><a href="javascript:;" reveal-id="ehac495-B59" data-open="ehac495-B59" class="link link-ref link-reveal xref-bibr">59</a></sup></td></tr><tr><td><span class="sans-serif">Angiopoietin-like protein 2 (ANGPTL2)</span></td><td><span class="sans-serif">Promotes renal inflammation and fibrosis</span></td><td><span class="sans-serif">Expressed in endothelial cells. Promotes oxidative stress, inflammation and fibrosis in the kidney and heart.</span><sup><span class="xrefLink" id="jumplink-ehac495-B60"></span><a href="javascript:;" reveal-id="ehac495-B60" data-open="ehac495-B60" class="link link-ref link-reveal xref-bibr">60</a>,<span class="xrefLink" id="jumplink-ehac495-B61"></span><a href="javascript:;" reveal-id="ehac495-B61" data-open="ehac495-B61" class="link link-ref link-reveal xref-bibr">61</a></sup><span class="sans-serif">May act as a marker of increased HIF-1</span>α <span class="sans-serif">activity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B62"></span><a href="javascript:;" reveal-id="ehac495-B62" data-open="ehac495-B62" class="link link-ref link-reveal xref-bibr">62</a></sup></td></tr><tr><td colspan="3"><span class="sans-serif"><strong>Proteins With Effects Other Than on the Heart and Kidneys</strong></span></td></tr><tr><td><span class="sans-serif">Promotilin (MLN)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Prohormone for motilin, which promotes gastrointestinal motility. Produces relaxation of vascular smooth muscle, leading to systemic vasodilatation</span></td></tr><tr><td><span class="sans-serif">Serine proteases inhibitor Kazal-type 1 (SPINK1)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Inhibits trypsin with proposed role in the pathogenesis of pancreatitis. May be biomarker of renal function, since it increases in proportion to decreases in glomerular filtration rate</span></td></tr><tr><td><span class="sans-serif">C–C motif chemokine 18 (CCL18)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in lung, antigen-presenting dendritic cells and M2 macrophages and is chemoattractant for</span><br /><span class="sans-serif">T cells and lymphocytes</span></td></tr><tr><td><span class="sans-serif">C–C motif chemokine 27 (CCL 27)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in skin and mediates homing of memory T lymphocytes to cutaneous sites</span></td></tr><tr><td><span class="sans-serif">Cystatin-F (CYTF, CST6)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Inhibits cathepsin C-directed protease. Expressed in immune cells and causes down-regulation of killing efficiency of cytotoxic T lymphocytes</span></td></tr><tr><td><span class="sans-serif">Scavenger receptor cysteine-rich domain-containing group B protein (SRCR)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in epithelial cells and plays a role in mucosal immunity and innate defence</span></td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Protein<span aria-hidden="true" style="display: none;"> . </span></th><th>Cellular action<span aria-hidden="true" style="display: none;"> . </span></th><th>Effects on heart, kidney, and other Sites<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="3"><span class="sans-serif"><strong>Proteins with effects on the heart</strong></span></td></tr><tr><td><span class="sans-serif">Insulin-like growth factor-binding protein 1 (IGFBP1)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy</span></td><td><span class="sans-serif">IGF1 promotes heart failure by inhibiting cardiac autophagy; increases in IGFBP1 interfere with actions of IGF1, thus promoting autophagy.</span><sup><span class="xrefLink" id="jumplink-ehac495-B10"></span><a href="javascript:;" reveal-id="ehac495-B10" data-open="ehac495-B10" class="link link-ref link-reveal xref-bibr">10</a></sup><span class="sans-serif">IGFBP1 also promotes HIF-1</span>α <span class="sans-serif">stability and inhibits cardiomyocyte apoptosis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B11"></span><a href="javascript:;" reveal-id="ehac495-B11" data-open="ehac495-B11" class="link link-ref link-reveal xref-bibr">11</a></sup><span class="sans-serif">Expression of IGFBP1 is upregulated by sirtuin-1.</span><sup><span class="xrefLink" id="jumplink-ehac495-B12"></span><a href="javascript:;" reveal-id="ehac495-B12" data-open="ehac495-B12" class="link link-ref link-reveal xref-bibr">12</a></sup></td></tr><tr><td><span class="sans-serif">Transferrin receptor protein 1 (TfRI)</span></td><td><span class="sans-serif">Promotion of cardiac iron metabolism and cardiac autophagy; improved mitochondrial health</span></td><td><span class="sans-serif">Required for iron transport into cardiomyocytes. TfR1 knockout leads to mitochondrial dysfunction, down-regulation of cardiac autophagy proteins and cardiomyopathy, which can be prevented by sirtuin-1 activation.</span><sup><span class="xrefLink" id="jumplink-ehac495-B13"></span><a href="javascript:;" reveal-id="ehac495-B13" data-open="ehac495-B13" class="link link-ref link-reveal xref-bibr">13</a></sup><span class="sans-serif">TfR1-mediated changes in transmembrane electron transport provides NAD + required for sirtuin activation.</span><sup><span class="xrefLink" id="jumplink-ehac495-B14"></span><a href="javascript:;" reveal-id="ehac495-B14" data-open="ehac495-B14" class="link link-ref link-reveal xref-bibr">14</a></sup></td></tr><tr><td><span class="sans-serif">Erythropoietin (EPO)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy and inhibition of cardiac fibrosis</span></td><td><span class="sans-serif">Prevents cardiac remodelling, resulting from promotion of autophagy and mitigates apoptosis and inflammation and fibrosis in the heart.</span><sup><span class="xrefLink" id="jumplink-ehac495-B15 ehac495-B16 ehac495-B17"></span><a href="javascript:;" reveal-id="ehac495-B15 ehac495-B16 ehac495-B17" data-open="ehac495-B15 ehac495-B16 ehac495-B17" class="link link-ref link-reveal xref-bibr">15–17</a></sup><span class="sans-serif">Expression and actions are AMPK- and sirtuin-dependent.</span><sup><span class="xrefLink" id="jumplink-ehac495-B15"></span><a href="javascript:;" reveal-id="ehac495-B15" data-open="ehac495-B15" class="link link-ref link-reveal xref-bibr">15</a>,<span class="xrefLink" id="jumplink-ehac495-B17"></span><a href="javascript:;" reveal-id="ehac495-B17" data-open="ehac495-B17" class="link link-ref link-reveal xref-bibr">17</a>,<span class="xrefLink" id="jumplink-ehac495-B18"></span><a href="javascript:;" reveal-id="ehac495-B18" data-open="ehac495-B18" class="link link-ref link-reveal xref-bibr">18</a></sup></td></tr><tr><td><span class="sans-serif">Follistatin (FST)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy</span></td><td><span class="sans-serif">Follistatin and follistatin-like proteins interact with the same receptors. Follistatin-like protein 1 reduces myocardial injury, apoptosis, remodelling, hypertrophy, and fibrosis by promoting autophagy through effects on AMPK.</span><sup><span class="xrefLink" id="jumplink-ehac495-B19"></span><a href="javascript:;" reveal-id="ehac495-B19" data-open="ehac495-B19" class="link link-ref link-reveal xref-bibr">19</a>,<span class="xrefLink" id="jumplink-ehac495-B20"></span><a href="javascript:;" reveal-id="ehac495-B20" data-open="ehac495-B20" class="link link-ref link-reveal xref-bibr">20</a></sup></td></tr><tr><td><span class="sans-serif">Retinol-binding protein 2 (RBP2)</span></td><td><span class="sans-serif">Promotion of renal autophagy; inhibition of cardiac apoptosis and enhanced cardiac regenerative capacity</span></td><td><span class="sans-serif">Retinoic acid levels decline in heart failure. Facilitates dietary retinol uptake, thereby mitigating cardiomyocyte apoptosis and promoting cardiac regenerative capacity.</span><sup>21–23</sup><span class="sans-serif">Prevents renal injury by promoting autophagy in the kidney.</span><sup><span class="xrefLink" id="jumplink-ehac495-B24"></span><a href="javascript:;" reveal-id="ehac495-B24" data-open="ehac495-B24" class="link link-ref link-reveal xref-bibr">24</a></sup></td></tr><tr><td><span class="sans-serif">Midkine (Mdk)</span></td><td><span class="sans-serif">Inhibition of cardiac apoptosis</span></td><td><span class="sans-serif">Reduces cardiac injury, mitigation of cardiac apoptosis and remodelling; promotes angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B25"></span><a href="javascript:;" reveal-id="ehac495-B25" data-open="ehac495-B25" class="link link-ref link-reveal xref-bibr">25</a>,<span class="xrefLink" id="jumplink-ehac495-B26"></span><a href="javascript:;" reveal-id="ehac495-B26" data-open="ehac495-B26" class="link link-ref link-reveal xref-bibr">26</a></sup></td></tr><tr><td><span class="sans-serif">Phospholipase A2, membrane-associated (PLA2)</span></td><td><span class="sans-serif">Promotion of cardiac repair following oxidative stress</span></td><td><span class="sans-serif">Calcium-independent PLA2 in ventricular cardiomyocytes localizes to mitochondria and peroxisomes and acts as a phospholipid repair enzyme following oxidative damage. Inhibition of phospholipase A2 is a mechanism underlying anthracycline cardiotoxicity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B27"></span><a href="javascript:;" reveal-id="ehac495-B27" data-open="ehac495-B27" class="link link-ref link-reveal xref-bibr">27</a>,<span class="xrefLink" id="jumplink-ehac495-B28"></span><a href="javascript:;" reveal-id="ehac495-B28" data-open="ehac495-B28" class="link link-ref link-reveal xref-bibr">28</a></sup></td></tr><tr><td><span class="sans-serif">Angiopoietin-related protein 4 (ANGPTL4)</span></td><td><span class="sans-serif">Reduction of oxidative stress and promotion of endothelial cell autophagy</span></td><td><span class="sans-serif">Inhibits lipoprotein lipase in cardiomyocytes. Prevents fatty acid-induced oxidative stress.</span><sup><span class="xrefLink" id="jumplink-ehac495-B29"></span><a href="javascript:;" reveal-id="ehac495-B29" data-open="ehac495-B29" class="link link-ref link-reveal xref-bibr">29</a></sup><span class="sans-serif">Preserves endothelial integrity by promotion of autophagy, thereby supporting myocardial function.</span><sup><span class="xrefLink" id="jumplink-ehac495-B30"></span><a href="javascript:;" reveal-id="ehac495-B30" data-open="ehac495-B30" class="link link-ref link-reveal xref-bibr">30</a></sup></td></tr><tr><td><span class="sans-serif">Insulin-like growth factor-binding protein 4 (IGFBP4)</span></td><td><span class="sans-serif">Reduction of oxidative stress and promotion of cardiac regenerative capacity</span></td><td><span class="sans-serif">Produces cardioprotection by minimizing the DNA injury produced by oxidative stress and promotes angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B31"></span><a href="javascript:;" reveal-id="ehac495-B31" data-open="ehac495-B31" class="link link-ref link-reveal xref-bibr">31</a></sup><span class="sans-serif">Enhances induction of cardiomyocytes from pluripotential stem cells by inhibition of the Wnt/β-catenin signalling, independent of its binding to IGF.</span><sup><span class="xrefLink" id="jumplink-ehac495-B32"></span><a href="javascript:;" reveal-id="ehac495-B32" data-open="ehac495-B32" class="link link-ref link-reveal xref-bibr">32</a></sup></td></tr><tr><td><span class="sans-serif">Protein-glutamine gamma-glutamyltransferase 2 (TGM2)</span></td><td><span class="sans-serif">Enhanced cardiac ATP synthesis, cardiac repair and regenerative capacity</span></td><td><span class="sans-serif">Enhanced fatty acid utilization and ATP synthesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B33"></span><a href="javascript:;" reveal-id="ehac495-B33" data-open="ehac495-B33" class="link link-ref link-reveal xref-bibr">33</a></sup><span class="sans-serif">Promotes cardiac repair and regenerative capacity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B34"></span><a href="javascript:;" reveal-id="ehac495-B34" data-open="ehac495-B34" class="link link-ref link-reveal xref-bibr">34</a></sup></td></tr><tr><td><span class="sans-serif">Mitochondrial creatine kinase, U-type (uMtCK)</span></td><td><span class="sans-serif">Support of cardiac energy metabolism</span></td><td><span class="sans-serif">Mediates the transfer of high energy phosphate from mitochondria to cytosol. Compensatory increase following oxidative stress has cardioprotective effects.</span><sup><span class="xrefLink" id="jumplink-ehac495-B35 ehac495-B36 ehac495-B37"></span><a href="javascript:;" reveal-id="ehac495-B35 ehac495-B36 ehac495-B37" data-open="ehac495-B35 ehac495-B36 ehac495-B37" class="link link-ref link-reveal xref-bibr">35–37</a></sup></td></tr><tr><td><span class="sans-serif">Connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed family member 5 (CCN5)</span></td><td><span class="sans-serif">Inhibition of cardiac fibrosis</span></td><td><span class="sans-serif">Inhibits cardiac hypertrophy. Interferes with endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, thereby reducing cardiac fibrosis. Prevents structural and electrical remodelling. Knockout leads to cardiomyopathy.</span><sup><span class="xrefLink" id="jumplink-ehac495-B38"></span><a href="javascript:;" reveal-id="ehac495-B38" data-open="ehac495-B38" class="link link-ref link-reveal xref-bibr">38</a>,<span class="xrefLink" id="jumplink-ehac495-B39"></span><a href="javascript:;" reveal-id="ehac495-B39" data-open="ehac495-B39" class="link link-ref link-reveal xref-bibr">39</a></sup></td></tr><tr><td><span class="sans-serif">Adipocyte fatty acid-binding protein 4 (AFABP4)</span></td><td><span class="sans-serif">Suppression of cardiac contractility</span></td><td><span class="sans-serif">Lipid binding protein that reduces fatty acid uptake by myocardium, thus suppresses cardiac contractility.</span><sup><span class="xrefLink" id="jumplink-ehac495-B40"></span><a href="javascript:;" reveal-id="ehac495-B40" data-open="ehac495-B40" class="link link-ref link-reveal xref-bibr">40</a>,<span class="xrefLink" id="jumplink-ehac495-B41"></span><a href="javascript:;" reveal-id="ehac495-B41" data-open="ehac495-B41" class="link link-ref link-reveal xref-bibr">41</a></sup><span class="sans-serif">May act as indicator of increased sirtuin-1 signalling and autophagic flux</span>.<sup><span class="xrefLink" id="jumplink-ehac495-B42"></span><a href="javascript:;" reveal-id="ehac495-B42" data-open="ehac495-B42" class="link link-ref link-reveal xref-bibr">42</a></sup></td></tr><tr><td><span class="sans-serif">Retinoic acid receptor responder protein 2 (Rarres2, chemerin)</span></td><td><span class="sans-serif">Promotion of cardiac hypertrophy, apoptosis, and angiogenesis</span></td><td><span class="sans-serif">Adipokine that induces cardiomyocyte hypertrophy, apoptosis, and angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B43"></span><a href="javascript:;" reveal-id="ehac495-B43" data-open="ehac495-B43" class="link link-ref link-reveal xref-bibr">43</a>,<span class="xrefLink" id="jumplink-ehac495-B44"></span><a href="javascript:;" reveal-id="ehac495-B44" data-open="ehac495-B44" class="link link-ref link-reveal xref-bibr">44</a></sup><span class="sans-serif">May act as biomarker of renal function, being inversely related to glomerular filtration rate.</span><sup><span class="xrefLink" id="jumplink-ehac495-B45"></span><a href="javascript:;" reveal-id="ehac495-B45" data-open="ehac495-B45" class="link link-ref link-reveal xref-bibr">45</a></sup></td></tr><tr><td colspan="3"><span class="sans-serif"><strong>Proteins with effects on the kidneys</strong></span></td></tr><tr><td><span class="sans-serif">Carbonic anhydrase 2 (CA2)</span></td><td><span class="sans-serif">Renal tubular sodium, bicarbonate, and water homeostasis</span></td><td><span class="sans-serif">Binds to and enhances the activity of NHE3 in the proximal renal tubule.</span><sup><span class="xrefLink" id="jumplink-ehac495-B46"></span><a href="javascript:;" reveal-id="ehac495-B46" data-open="ehac495-B46" class="link link-ref link-reveal xref-bibr">46</a></sup><span class="sans-serif">May offset increases in urinary bicarbonate and water resulting from SGLT2 inhibition.</span></td></tr><tr><td><span class="sans-serif">Guanylin (GUCA)</span></td><td><span class="sans-serif">Renal tubular sodium transport</span></td><td><span class="sans-serif">After the dietary salt load, guanylin and uroguanylin promote natriuresis by inhibiting NHE3 in proximal tubule</span><sup><span class="xrefLink" id="jumplink-ehac495-B47"></span><a href="javascript:;" reveal-id="ehac495-B47" data-open="ehac495-B47" class="link link-ref link-reveal xref-bibr">47</a>,<span class="xrefLink" id="jumplink-ehac495-B48"></span><a href="javascript:;" reveal-id="ehac495-B48" data-open="ehac495-B48" class="link link-ref link-reveal xref-bibr">48</a></sup></td></tr><tr><td><span class="sans-serif">Uromodulin (UMOD)</span></td><td><span class="sans-serif">Renal tubular sodium transport and muting of renal inflammation</span></td><td><span class="sans-serif">Promotes sodium reabsorption in the thick ascending limb of the loop of Henle.</span><sup><span class="xrefLink" id="jumplink-ehac495-B49"></span><a href="javascript:;" reveal-id="ehac495-B49" data-open="ehac495-B49" class="link link-ref link-reveal xref-bibr">49</a>,<span class="xrefLink" id="jumplink-ehac495-B50"></span><a href="javascript:;" reveal-id="ehac495-B50" data-open="ehac495-B50" class="link link-ref link-reveal xref-bibr">50</a></sup><span class="sans-serif">Acts as a trap for proinflammatory renal cytokines; loss-of-function mutations lead to chronic kidney disease.</span><sup><span class="xrefLink" id="jumplink-ehac495-B51"></span><a href="javascript:;" reveal-id="ehac495-B51" data-open="ehac495-B51" class="link link-ref link-reveal xref-bibr">51</a></sup></td></tr><tr><td><span class="sans-serif">Kidney injury molecule-1 (KIM-1)</span></td><td><span class="sans-serif">Promotion of renal proximal tubular injury, inflammation, and fibrosis</span></td><td><span class="sans-serif">Mediates renal tubular cell injury and apoptosis and promotes tubulointerstitial inflammation and fibrosis</span><sup><span class="xrefLink" id="jumplink-ehac495-B52 ehac495-B53 ehac495-B54"></span><a href="javascript:;" reveal-id="ehac495-B52 ehac495-B53 ehac495-B54" data-open="ehac495-B52 ehac495-B53 ehac495-B54" class="link link-ref link-reveal xref-bibr">52–54</a></sup></td></tr><tr><td><span class="sans-serif">Epithelial cell adhesion molecule (EpCAM)</span></td><td><span class="sans-serif">Promotion of renal tubular integrity and regeneration</span></td><td><span class="sans-serif">Promotes adhesion and polarity of renal tubular cells. EpCAM is suppressed by nephrotoxic agents and is enhanced during renal tubular regeneration</span><sup><span class="xrefLink" id="jumplink-ehac495-B55"></span><a href="javascript:;" reveal-id="ehac495-B55" data-open="ehac495-B55" class="link link-ref link-reveal xref-bibr">55</a>,<span class="xrefLink" id="jumplink-ehac495-B56"></span><a href="javascript:;" reveal-id="ehac495-B56" data-open="ehac495-B56" class="link link-ref link-reveal xref-bibr">56</a></sup></td></tr><tr><td><span class="sans-serif">Thymosin beta-10 (TMSB10)</span></td><td><span class="sans-serif">Promotion of renal tubular integrity and regeneration</span></td><td><span class="sans-serif">Plays important role in organization of cytoskeleton, thus promoting adhesion and polarity of renal parenchymal cells</span><sup><span class="xrefLink" id="jumplink-ehac495-B57"></span><a href="javascript:;" reveal-id="ehac495-B57" data-open="ehac495-B57" class="link link-ref link-reveal xref-bibr">57</a>,<span class="xrefLink" id="jumplink-ehac495-B58"></span><a href="javascript:;" reveal-id="ehac495-B58" data-open="ehac495-B58" class="link link-ref link-reveal xref-bibr">58</a></sup></td></tr><tr><td><span class="sans-serif">Beta-Ala-His dipeptidase (carnosinase 1, CNDP1)</span></td><td><span class="sans-serif">Degradation of nephroprotective carnosine</span></td><td><span class="sans-serif">Carnosine protects against the development of nephropathy, and gain-of-function mutations of carnosinase-1 cause carnosine depletion and increase risk of chronic kidney disease.</span><sup><span class="xrefLink" id="jumplink-ehac495-B59"></span><a href="javascript:;" reveal-id="ehac495-B59" data-open="ehac495-B59" class="link link-ref link-reveal xref-bibr">59</a></sup></td></tr><tr><td><span class="sans-serif">Angiopoietin-like protein 2 (ANGPTL2)</span></td><td><span class="sans-serif">Promotes renal inflammation and fibrosis</span></td><td><span class="sans-serif">Expressed in endothelial cells. Promotes oxidative stress, inflammation and fibrosis in the kidney and heart.</span><sup><span class="xrefLink" id="jumplink-ehac495-B60"></span><a href="javascript:;" reveal-id="ehac495-B60" data-open="ehac495-B60" class="link link-ref link-reveal xref-bibr">60</a>,<span class="xrefLink" id="jumplink-ehac495-B61"></span><a href="javascript:;" reveal-id="ehac495-B61" data-open="ehac495-B61" class="link link-ref link-reveal xref-bibr">61</a></sup><span class="sans-serif">May act as a marker of increased HIF-1</span>α <span class="sans-serif">activity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B62"></span><a href="javascript:;" reveal-id="ehac495-B62" data-open="ehac495-B62" class="link link-ref link-reveal xref-bibr">62</a></sup></td></tr><tr><td colspan="3"><span class="sans-serif"><strong>Proteins With Effects Other Than on the Heart and Kidneys</strong></span></td></tr><tr><td><span class="sans-serif">Promotilin (MLN)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Prohormone for motilin, which promotes gastrointestinal motility. Produces relaxation of vascular smooth muscle, leading to systemic vasodilatation</span></td></tr><tr><td><span class="sans-serif">Serine proteases inhibitor Kazal-type 1 (SPINK1)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Inhibits trypsin with proposed role in the pathogenesis of pancreatitis. May be biomarker of renal function, since it increases in proportion to decreases in glomerular filtration rate</span></td></tr><tr><td><span class="sans-serif">C–C motif chemokine 18 (CCL18)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in lung, antigen-presenting dendritic cells and M2 macrophages and is chemoattractant for</span><br /><span class="sans-serif">T cells and lymphocytes</span></td></tr><tr><td><span class="sans-serif">C–C motif chemokine 27 (CCL 27)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in skin and mediates homing of memory T lymphocytes to cutaneous sites</span></td></tr><tr><td><span class="sans-serif">Cystatin-F (CYTF, CST6)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Inhibits cathepsin C-directed protease. Expressed in immune cells and causes down-regulation of killing efficiency of cytotoxic T lymphocytes</span></td></tr><tr><td><span class="sans-serif">Scavenger receptor cysteine-rich domain-containing group B protein (SRCR)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in epithelial cells and plays a role in mucosal immunity and innate defence</span></td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-tblfn2"></span><div content-id="tblfn2" class="footnote"><span class="fn"><p class="chapter-para">RBP2 has effects on the heart and kidneys, but to avoid duplication, <em>t</em> is described only in the section on the heart.</p></span></div><span id="fn-tblfn3"></span><div content-id="tblfn3" class="footnote"><span class="fn"><p class="chapter-para">AMPK, adenosine monophosphate-activated protein kinase; ATP, adenosine triphosphate; IGF1, insulin-like growth factor 1; NAD+, nicotinamide adenine dinucleotide; NHE3, sodium–hydrogen exchanger isoform 3; Wnt, Wingless-related integration site glycoprotein; HIF-1α, hypoxia-inducible factor-1α.</p></span></div></div></div></div><div class="table-full-width-wrap"><div class="table-wrap table-wide standard-table"><div class="table-wrap-title" id="ehac495-T2" data-id="ehac495-T2"><span class="label title-label" id="label-32545">Table 2</span><div class="
 graphic-wrap table-open-button-wrap
 "><a class="fig-view-orig at-tableViewLarge openInAnotherWindow btn js-view-large" role="button" target="_blank" href="
 /view-large/388939882" aria-describedby="label-32545"> Open in new tab </a></div><div class="caption caption-id-" id="caption-32545"><p class="chapter-para">Biological effect of differentially expressed proteins on heart and kidney</p></div> </div><div class="table-overflow"><table role="table" aria-labelledby="
 label-32545" aria-describedby="
 caption-32545"><thead><tr><th>Protein<span aria-hidden="true" style="display: none;"> . </span></th><th>Cellular action<span aria-hidden="true" style="display: none;"> . </span></th><th>Effects on heart, kidney, and other Sites<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="3"><span class="sans-serif"><strong>Proteins with effects on the heart</strong></span></td></tr><tr><td><span class="sans-serif">Insulin-like growth factor-binding protein 1 (IGFBP1)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy</span></td><td><span class="sans-serif">IGF1 promotes heart failure by inhibiting cardiac autophagy; increases in IGFBP1 interfere with actions of IGF1, thus promoting autophagy.</span><sup><span class="xrefLink" id="jumplink-ehac495-B10"></span><a href="javascript:;" reveal-id="ehac495-B10" data-open="ehac495-B10" class="link link-ref link-reveal xref-bibr">10</a></sup><span class="sans-serif">IGFBP1 also promotes HIF-1</span>α <span class="sans-serif">stability and inhibits cardiomyocyte apoptosis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B11"></span><a href="javascript:;" reveal-id="ehac495-B11" data-open="ehac495-B11" class="link link-ref link-reveal xref-bibr">11</a></sup><span class="sans-serif">Expression of IGFBP1 is upregulated by sirtuin-1.</span><sup><span class="xrefLink" id="jumplink-ehac495-B12"></span><a href="javascript:;" reveal-id="ehac495-B12" data-open="ehac495-B12" class="link link-ref link-reveal xref-bibr">12</a></sup></td></tr><tr><td><span class="sans-serif">Transferrin receptor protein 1 (TfRI)</span></td><td><span class="sans-serif">Promotion of cardiac iron metabolism and cardiac autophagy; improved mitochondrial health</span></td><td><span class="sans-serif">Required for iron transport into cardiomyocytes. TfR1 knockout leads to mitochondrial dysfunction, down-regulation of cardiac autophagy proteins and cardiomyopathy, which can be prevented by sirtuin-1 activation.</span><sup><span class="xrefLink" id="jumplink-ehac495-B13"></span><a href="javascript:;" reveal-id="ehac495-B13" data-open="ehac495-B13" class="link link-ref link-reveal xref-bibr">13</a></sup><span class="sans-serif">TfR1-mediated changes in transmembrane electron transport provides NAD + required for sirtuin activation.</span><sup><span class="xrefLink" id="jumplink-ehac495-B14"></span><a href="javascript:;" reveal-id="ehac495-B14" data-open="ehac495-B14" class="link link-ref link-reveal xref-bibr">14</a></sup></td></tr><tr><td><span class="sans-serif">Erythropoietin (EPO)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy and inhibition of cardiac fibrosis</span></td><td><span class="sans-serif">Prevents cardiac remodelling, resulting from promotion of autophagy and mitigates apoptosis and inflammation and fibrosis in the heart.</span><sup><span class="xrefLink" id="jumplink-ehac495-B15 ehac495-B16 ehac495-B17"></span><a href="javascript:;" reveal-id="ehac495-B15 ehac495-B16 ehac495-B17" data-open="ehac495-B15 ehac495-B16 ehac495-B17" class="link link-ref link-reveal xref-bibr">15–17</a></sup><span class="sans-serif">Expression and actions are AMPK- and sirtuin-dependent.</span><sup><span class="xrefLink" id="jumplink-ehac495-B15"></span><a href="javascript:;" reveal-id="ehac495-B15" data-open="ehac495-B15" class="link link-ref link-reveal xref-bibr">15</a>,<span class="xrefLink" id="jumplink-ehac495-B17"></span><a href="javascript:;" reveal-id="ehac495-B17" data-open="ehac495-B17" class="link link-ref link-reveal xref-bibr">17</a>,<span class="xrefLink" id="jumplink-ehac495-B18"></span><a href="javascript:;" reveal-id="ehac495-B18" data-open="ehac495-B18" class="link link-ref link-reveal xref-bibr">18</a></sup></td></tr><tr><td><span class="sans-serif">Follistatin (FST)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy</span></td><td><span class="sans-serif">Follistatin and follistatin-like proteins interact with the same receptors. Follistatin-like protein 1 reduces myocardial injury, apoptosis, remodelling, hypertrophy, and fibrosis by promoting autophagy through effects on AMPK.</span><sup><span class="xrefLink" id="jumplink-ehac495-B19"></span><a href="javascript:;" reveal-id="ehac495-B19" data-open="ehac495-B19" class="link link-ref link-reveal xref-bibr">19</a>,<span class="xrefLink" id="jumplink-ehac495-B20"></span><a href="javascript:;" reveal-id="ehac495-B20" data-open="ehac495-B20" class="link link-ref link-reveal xref-bibr">20</a></sup></td></tr><tr><td><span class="sans-serif">Retinol-binding protein 2 (RBP2)</span></td><td><span class="sans-serif">Promotion of renal autophagy; inhibition of cardiac apoptosis and enhanced cardiac regenerative capacity</span></td><td><span class="sans-serif">Retinoic acid levels decline in heart failure. Facilitates dietary retinol uptake, thereby mitigating cardiomyocyte apoptosis and promoting cardiac regenerative capacity.</span><sup>21–23</sup><span class="sans-serif">Prevents renal injury by promoting autophagy in the kidney.</span><sup><span class="xrefLink" id="jumplink-ehac495-B24"></span><a href="javascript:;" reveal-id="ehac495-B24" data-open="ehac495-B24" class="link link-ref link-reveal xref-bibr">24</a></sup></td></tr><tr><td><span class="sans-serif">Midkine (Mdk)</span></td><td><span class="sans-serif">Inhibition of cardiac apoptosis</span></td><td><span class="sans-serif">Reduces cardiac injury, mitigation of cardiac apoptosis and remodelling; promotes angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B25"></span><a href="javascript:;" reveal-id="ehac495-B25" data-open="ehac495-B25" class="link link-ref link-reveal xref-bibr">25</a>,<span class="xrefLink" id="jumplink-ehac495-B26"></span><a href="javascript:;" reveal-id="ehac495-B26" data-open="ehac495-B26" class="link link-ref link-reveal xref-bibr">26</a></sup></td></tr><tr><td><span class="sans-serif">Phospholipase A2, membrane-associated (PLA2)</span></td><td><span class="sans-serif">Promotion of cardiac repair following oxidative stress</span></td><td><span class="sans-serif">Calcium-independent PLA2 in ventricular cardiomyocytes localizes to mitochondria and peroxisomes and acts as a phospholipid repair enzyme following oxidative damage. Inhibition of phospholipase A2 is a mechanism underlying anthracycline cardiotoxicity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B27"></span><a href="javascript:;" reveal-id="ehac495-B27" data-open="ehac495-B27" class="link link-ref link-reveal xref-bibr">27</a>,<span class="xrefLink" id="jumplink-ehac495-B28"></span><a href="javascript:;" reveal-id="ehac495-B28" data-open="ehac495-B28" class="link link-ref link-reveal xref-bibr">28</a></sup></td></tr><tr><td><span class="sans-serif">Angiopoietin-related protein 4 (ANGPTL4)</span></td><td><span class="sans-serif">Reduction of oxidative stress and promotion of endothelial cell autophagy</span></td><td><span class="sans-serif">Inhibits lipoprotein lipase in cardiomyocytes. Prevents fatty acid-induced oxidative stress.</span><sup><span class="xrefLink" id="jumplink-ehac495-B29"></span><a href="javascript:;" reveal-id="ehac495-B29" data-open="ehac495-B29" class="link link-ref link-reveal xref-bibr">29</a></sup><span class="sans-serif">Preserves endothelial integrity by promotion of autophagy, thereby supporting myocardial function.</span><sup><span class="xrefLink" id="jumplink-ehac495-B30"></span><a href="javascript:;" reveal-id="ehac495-B30" data-open="ehac495-B30" class="link link-ref link-reveal xref-bibr">30</a></sup></td></tr><tr><td><span class="sans-serif">Insulin-like growth factor-binding protein 4 (IGFBP4)</span></td><td><span class="sans-serif">Reduction of oxidative stress and promotion of cardiac regenerative capacity</span></td><td><span class="sans-serif">Produces cardioprotection by minimizing the DNA injury produced by oxidative stress and promotes angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B31"></span><a href="javascript:;" reveal-id="ehac495-B31" data-open="ehac495-B31" class="link link-ref link-reveal xref-bibr">31</a></sup><span class="sans-serif">Enhances induction of cardiomyocytes from pluripotential stem cells by inhibition of the Wnt/β-catenin signalling, independent of its binding to IGF.</span><sup><span class="xrefLink" id="jumplink-ehac495-B32"></span><a href="javascript:;" reveal-id="ehac495-B32" data-open="ehac495-B32" class="link link-ref link-reveal xref-bibr">32</a></sup></td></tr><tr><td><span class="sans-serif">Protein-glutamine gamma-glutamyltransferase 2 (TGM2)</span></td><td><span class="sans-serif">Enhanced cardiac ATP synthesis, cardiac repair and regenerative capacity</span></td><td><span class="sans-serif">Enhanced fatty acid utilization and ATP synthesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B33"></span><a href="javascript:;" reveal-id="ehac495-B33" data-open="ehac495-B33" class="link link-ref link-reveal xref-bibr">33</a></sup><span class="sans-serif">Promotes cardiac repair and regenerative capacity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B34"></span><a href="javascript:;" reveal-id="ehac495-B34" data-open="ehac495-B34" class="link link-ref link-reveal xref-bibr">34</a></sup></td></tr><tr><td><span class="sans-serif">Mitochondrial creatine kinase, U-type (uMtCK)</span></td><td><span class="sans-serif">Support of cardiac energy metabolism</span></td><td><span class="sans-serif">Mediates the transfer of high energy phosphate from mitochondria to cytosol. Compensatory increase following oxidative stress has cardioprotective effects.</span><sup><span class="xrefLink" id="jumplink-ehac495-B35 ehac495-B36 ehac495-B37"></span><a href="javascript:;" reveal-id="ehac495-B35 ehac495-B36 ehac495-B37" data-open="ehac495-B35 ehac495-B36 ehac495-B37" class="link link-ref link-reveal xref-bibr">35–37</a></sup></td></tr><tr><td><span class="sans-serif">Connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed family member 5 (CCN5)</span></td><td><span class="sans-serif">Inhibition of cardiac fibrosis</span></td><td><span class="sans-serif">Inhibits cardiac hypertrophy. Interferes with endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, thereby reducing cardiac fibrosis. Prevents structural and electrical remodelling. Knockout leads to cardiomyopathy.</span><sup><span class="xrefLink" id="jumplink-ehac495-B38"></span><a href="javascript:;" reveal-id="ehac495-B38" data-open="ehac495-B38" class="link link-ref link-reveal xref-bibr">38</a>,<span class="xrefLink" id="jumplink-ehac495-B39"></span><a href="javascript:;" reveal-id="ehac495-B39" data-open="ehac495-B39" class="link link-ref link-reveal xref-bibr">39</a></sup></td></tr><tr><td><span class="sans-serif">Adipocyte fatty acid-binding protein 4 (AFABP4)</span></td><td><span class="sans-serif">Suppression of cardiac contractility</span></td><td><span class="sans-serif">Lipid binding protein that reduces fatty acid uptake by myocardium, thus suppresses cardiac contractility.</span><sup><span class="xrefLink" id="jumplink-ehac495-B40"></span><a href="javascript:;" reveal-id="ehac495-B40" data-open="ehac495-B40" class="link link-ref link-reveal xref-bibr">40</a>,<span class="xrefLink" id="jumplink-ehac495-B41"></span><a href="javascript:;" reveal-id="ehac495-B41" data-open="ehac495-B41" class="link link-ref link-reveal xref-bibr">41</a></sup><span class="sans-serif">May act as indicator of increased sirtuin-1 signalling and autophagic flux</span>.<sup><span class="xrefLink" id="jumplink-ehac495-B42"></span><a href="javascript:;" reveal-id="ehac495-B42" data-open="ehac495-B42" class="link link-ref link-reveal xref-bibr">42</a></sup></td></tr><tr><td><span class="sans-serif">Retinoic acid receptor responder protein 2 (Rarres2, chemerin)</span></td><td><span class="sans-serif">Promotion of cardiac hypertrophy, apoptosis, and angiogenesis</span></td><td><span class="sans-serif">Adipokine that induces cardiomyocyte hypertrophy, apoptosis, and angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B43"></span><a href="javascript:;" reveal-id="ehac495-B43" data-open="ehac495-B43" class="link link-ref link-reveal xref-bibr">43</a>,<span class="xrefLink" id="jumplink-ehac495-B44"></span><a href="javascript:;" reveal-id="ehac495-B44" data-open="ehac495-B44" class="link link-ref link-reveal xref-bibr">44</a></sup><span class="sans-serif">May act as biomarker of renal function, being inversely related to glomerular filtration rate.</span><sup><span class="xrefLink" id="jumplink-ehac495-B45"></span><a href="javascript:;" reveal-id="ehac495-B45" data-open="ehac495-B45" class="link link-ref link-reveal xref-bibr">45</a></sup></td></tr><tr><td colspan="3"><span class="sans-serif"><strong>Proteins with effects on the kidneys</strong></span></td></tr><tr><td><span class="sans-serif">Carbonic anhydrase 2 (CA2)</span></td><td><span class="sans-serif">Renal tubular sodium, bicarbonate, and water homeostasis</span></td><td><span class="sans-serif">Binds to and enhances the activity of NHE3 in the proximal renal tubule.</span><sup><span class="xrefLink" id="jumplink-ehac495-B46"></span><a href="javascript:;" reveal-id="ehac495-B46" data-open="ehac495-B46" class="link link-ref link-reveal xref-bibr">46</a></sup><span class="sans-serif">May offset increases in urinary bicarbonate and water resulting from SGLT2 inhibition.</span></td></tr><tr><td><span class="sans-serif">Guanylin (GUCA)</span></td><td><span class="sans-serif">Renal tubular sodium transport</span></td><td><span class="sans-serif">After the dietary salt load, guanylin and uroguanylin promote natriuresis by inhibiting NHE3 in proximal tubule</span><sup><span class="xrefLink" id="jumplink-ehac495-B47"></span><a href="javascript:;" reveal-id="ehac495-B47" data-open="ehac495-B47" class="link link-ref link-reveal xref-bibr">47</a>,<span class="xrefLink" id="jumplink-ehac495-B48"></span><a href="javascript:;" reveal-id="ehac495-B48" data-open="ehac495-B48" class="link link-ref link-reveal xref-bibr">48</a></sup></td></tr><tr><td><span class="sans-serif">Uromodulin (UMOD)</span></td><td><span class="sans-serif">Renal tubular sodium transport and muting of renal inflammation</span></td><td><span class="sans-serif">Promotes sodium reabsorption in the thick ascending limb of the loop of Henle.</span><sup><span class="xrefLink" id="jumplink-ehac495-B49"></span><a href="javascript:;" reveal-id="ehac495-B49" data-open="ehac495-B49" class="link link-ref link-reveal xref-bibr">49</a>,<span class="xrefLink" id="jumplink-ehac495-B50"></span><a href="javascript:;" reveal-id="ehac495-B50" data-open="ehac495-B50" class="link link-ref link-reveal xref-bibr">50</a></sup><span class="sans-serif">Acts as a trap for proinflammatory renal cytokines; loss-of-function mutations lead to chronic kidney disease.</span><sup><span class="xrefLink" id="jumplink-ehac495-B51"></span><a href="javascript:;" reveal-id="ehac495-B51" data-open="ehac495-B51" class="link link-ref link-reveal xref-bibr">51</a></sup></td></tr><tr><td><span class="sans-serif">Kidney injury molecule-1 (KIM-1)</span></td><td><span class="sans-serif">Promotion of renal proximal tubular injury, inflammation, and fibrosis</span></td><td><span class="sans-serif">Mediates renal tubular cell injury and apoptosis and promotes tubulointerstitial inflammation and fibrosis</span><sup><span class="xrefLink" id="jumplink-ehac495-B52 ehac495-B53 ehac495-B54"></span><a href="javascript:;" reveal-id="ehac495-B52 ehac495-B53 ehac495-B54" data-open="ehac495-B52 ehac495-B53 ehac495-B54" class="link link-ref link-reveal xref-bibr">52–54</a></sup></td></tr><tr><td><span class="sans-serif">Epithelial cell adhesion molecule (EpCAM)</span></td><td><span class="sans-serif">Promotion of renal tubular integrity and regeneration</span></td><td><span class="sans-serif">Promotes adhesion and polarity of renal tubular cells. EpCAM is suppressed by nephrotoxic agents and is enhanced during renal tubular regeneration</span><sup><span class="xrefLink" id="jumplink-ehac495-B55"></span><a href="javascript:;" reveal-id="ehac495-B55" data-open="ehac495-B55" class="link link-ref link-reveal xref-bibr">55</a>,<span class="xrefLink" id="jumplink-ehac495-B56"></span><a href="javascript:;" reveal-id="ehac495-B56" data-open="ehac495-B56" class="link link-ref link-reveal xref-bibr">56</a></sup></td></tr><tr><td><span class="sans-serif">Thymosin beta-10 (TMSB10)</span></td><td><span class="sans-serif">Promotion of renal tubular integrity and regeneration</span></td><td><span class="sans-serif">Plays important role in organization of cytoskeleton, thus promoting adhesion and polarity of renal parenchymal cells</span><sup><span class="xrefLink" id="jumplink-ehac495-B57"></span><a href="javascript:;" reveal-id="ehac495-B57" data-open="ehac495-B57" class="link link-ref link-reveal xref-bibr">57</a>,<span class="xrefLink" id="jumplink-ehac495-B58"></span><a href="javascript:;" reveal-id="ehac495-B58" data-open="ehac495-B58" class="link link-ref link-reveal xref-bibr">58</a></sup></td></tr><tr><td><span class="sans-serif">Beta-Ala-His dipeptidase (carnosinase 1, CNDP1)</span></td><td><span class="sans-serif">Degradation of nephroprotective carnosine</span></td><td><span class="sans-serif">Carnosine protects against the development of nephropathy, and gain-of-function mutations of carnosinase-1 cause carnosine depletion and increase risk of chronic kidney disease.</span><sup><span class="xrefLink" id="jumplink-ehac495-B59"></span><a href="javascript:;" reveal-id="ehac495-B59" data-open="ehac495-B59" class="link link-ref link-reveal xref-bibr">59</a></sup></td></tr><tr><td><span class="sans-serif">Angiopoietin-like protein 2 (ANGPTL2)</span></td><td><span class="sans-serif">Promotes renal inflammation and fibrosis</span></td><td><span class="sans-serif">Expressed in endothelial cells. Promotes oxidative stress, inflammation and fibrosis in the kidney and heart.</span><sup><span class="xrefLink" id="jumplink-ehac495-B60"></span><a href="javascript:;" reveal-id="ehac495-B60" data-open="ehac495-B60" class="link link-ref link-reveal xref-bibr">60</a>,<span class="xrefLink" id="jumplink-ehac495-B61"></span><a href="javascript:;" reveal-id="ehac495-B61" data-open="ehac495-B61" class="link link-ref link-reveal xref-bibr">61</a></sup><span class="sans-serif">May act as a marker of increased HIF-1</span>α <span class="sans-serif">activity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B62"></span><a href="javascript:;" reveal-id="ehac495-B62" data-open="ehac495-B62" class="link link-ref link-reveal xref-bibr">62</a></sup></td></tr><tr><td colspan="3"><span class="sans-serif"><strong>Proteins With Effects Other Than on the Heart and Kidneys</strong></span></td></tr><tr><td><span class="sans-serif">Promotilin (MLN)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Prohormone for motilin, which promotes gastrointestinal motility. Produces relaxation of vascular smooth muscle, leading to systemic vasodilatation</span></td></tr><tr><td><span class="sans-serif">Serine proteases inhibitor Kazal-type 1 (SPINK1)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Inhibits trypsin with proposed role in the pathogenesis of pancreatitis. May be biomarker of renal function, since it increases in proportion to decreases in glomerular filtration rate</span></td></tr><tr><td><span class="sans-serif">C–C motif chemokine 18 (CCL18)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in lung, antigen-presenting dendritic cells and M2 macrophages and is chemoattractant for</span><br /><span class="sans-serif">T cells and lymphocytes</span></td></tr><tr><td><span class="sans-serif">C–C motif chemokine 27 (CCL 27)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in skin and mediates homing of memory T lymphocytes to cutaneous sites</span></td></tr><tr><td><span class="sans-serif">Cystatin-F (CYTF, CST6)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Inhibits cathepsin C-directed protease. Expressed in immune cells and causes down-regulation of killing efficiency of cytotoxic T lymphocytes</span></td></tr><tr><td><span class="sans-serif">Scavenger receptor cysteine-rich domain-containing group B protein (SRCR)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in epithelial cells and plays a role in mucosal immunity and innate defence</span></td></tr></tbody></table></div><div class="table-modal"><table><thead><tr><th>Protein<span aria-hidden="true" style="display: none;"> . </span></th><th>Cellular action<span aria-hidden="true" style="display: none;"> . </span></th><th>Effects on heart, kidney, and other Sites<span aria-hidden="true" style="display: none;"> . </span></th></tr></thead><tbody><tr><td colspan="3"><span class="sans-serif"><strong>Proteins with effects on the heart</strong></span></td></tr><tr><td><span class="sans-serif">Insulin-like growth factor-binding protein 1 (IGFBP1)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy</span></td><td><span class="sans-serif">IGF1 promotes heart failure by inhibiting cardiac autophagy; increases in IGFBP1 interfere with actions of IGF1, thus promoting autophagy.</span><sup><span class="xrefLink" id="jumplink-ehac495-B10"></span><a href="javascript:;" reveal-id="ehac495-B10" data-open="ehac495-B10" class="link link-ref link-reveal xref-bibr">10</a></sup><span class="sans-serif">IGFBP1 also promotes HIF-1</span>α <span class="sans-serif">stability and inhibits cardiomyocyte apoptosis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B11"></span><a href="javascript:;" reveal-id="ehac495-B11" data-open="ehac495-B11" class="link link-ref link-reveal xref-bibr">11</a></sup><span class="sans-serif">Expression of IGFBP1 is upregulated by sirtuin-1.</span><sup><span class="xrefLink" id="jumplink-ehac495-B12"></span><a href="javascript:;" reveal-id="ehac495-B12" data-open="ehac495-B12" class="link link-ref link-reveal xref-bibr">12</a></sup></td></tr><tr><td><span class="sans-serif">Transferrin receptor protein 1 (TfRI)</span></td><td><span class="sans-serif">Promotion of cardiac iron metabolism and cardiac autophagy; improved mitochondrial health</span></td><td><span class="sans-serif">Required for iron transport into cardiomyocytes. TfR1 knockout leads to mitochondrial dysfunction, down-regulation of cardiac autophagy proteins and cardiomyopathy, which can be prevented by sirtuin-1 activation.</span><sup><span class="xrefLink" id="jumplink-ehac495-B13"></span><a href="javascript:;" reveal-id="ehac495-B13" data-open="ehac495-B13" class="link link-ref link-reveal xref-bibr">13</a></sup><span class="sans-serif">TfR1-mediated changes in transmembrane electron transport provides NAD + required for sirtuin activation.</span><sup><span class="xrefLink" id="jumplink-ehac495-B14"></span><a href="javascript:;" reveal-id="ehac495-B14" data-open="ehac495-B14" class="link link-ref link-reveal xref-bibr">14</a></sup></td></tr><tr><td><span class="sans-serif">Erythropoietin (EPO)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy and inhibition of cardiac fibrosis</span></td><td><span class="sans-serif">Prevents cardiac remodelling, resulting from promotion of autophagy and mitigates apoptosis and inflammation and fibrosis in the heart.</span><sup><span class="xrefLink" id="jumplink-ehac495-B15 ehac495-B16 ehac495-B17"></span><a href="javascript:;" reveal-id="ehac495-B15 ehac495-B16 ehac495-B17" data-open="ehac495-B15 ehac495-B16 ehac495-B17" class="link link-ref link-reveal xref-bibr">15–17</a></sup><span class="sans-serif">Expression and actions are AMPK- and sirtuin-dependent.</span><sup><span class="xrefLink" id="jumplink-ehac495-B15"></span><a href="javascript:;" reveal-id="ehac495-B15" data-open="ehac495-B15" class="link link-ref link-reveal xref-bibr">15</a>,<span class="xrefLink" id="jumplink-ehac495-B17"></span><a href="javascript:;" reveal-id="ehac495-B17" data-open="ehac495-B17" class="link link-ref link-reveal xref-bibr">17</a>,<span class="xrefLink" id="jumplink-ehac495-B18"></span><a href="javascript:;" reveal-id="ehac495-B18" data-open="ehac495-B18" class="link link-ref link-reveal xref-bibr">18</a></sup></td></tr><tr><td><span class="sans-serif">Follistatin (FST)</span></td><td><span class="sans-serif">Promotion of cardiac autophagy</span></td><td><span class="sans-serif">Follistatin and follistatin-like proteins interact with the same receptors. Follistatin-like protein 1 reduces myocardial injury, apoptosis, remodelling, hypertrophy, and fibrosis by promoting autophagy through effects on AMPK.</span><sup><span class="xrefLink" id="jumplink-ehac495-B19"></span><a href="javascript:;" reveal-id="ehac495-B19" data-open="ehac495-B19" class="link link-ref link-reveal xref-bibr">19</a>,<span class="xrefLink" id="jumplink-ehac495-B20"></span><a href="javascript:;" reveal-id="ehac495-B20" data-open="ehac495-B20" class="link link-ref link-reveal xref-bibr">20</a></sup></td></tr><tr><td><span class="sans-serif">Retinol-binding protein 2 (RBP2)</span></td><td><span class="sans-serif">Promotion of renal autophagy; inhibition of cardiac apoptosis and enhanced cardiac regenerative capacity</span></td><td><span class="sans-serif">Retinoic acid levels decline in heart failure. Facilitates dietary retinol uptake, thereby mitigating cardiomyocyte apoptosis and promoting cardiac regenerative capacity.</span><sup>21–23</sup><span class="sans-serif">Prevents renal injury by promoting autophagy in the kidney.</span><sup><span class="xrefLink" id="jumplink-ehac495-B24"></span><a href="javascript:;" reveal-id="ehac495-B24" data-open="ehac495-B24" class="link link-ref link-reveal xref-bibr">24</a></sup></td></tr><tr><td><span class="sans-serif">Midkine (Mdk)</span></td><td><span class="sans-serif">Inhibition of cardiac apoptosis</span></td><td><span class="sans-serif">Reduces cardiac injury, mitigation of cardiac apoptosis and remodelling; promotes angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B25"></span><a href="javascript:;" reveal-id="ehac495-B25" data-open="ehac495-B25" class="link link-ref link-reveal xref-bibr">25</a>,<span class="xrefLink" id="jumplink-ehac495-B26"></span><a href="javascript:;" reveal-id="ehac495-B26" data-open="ehac495-B26" class="link link-ref link-reveal xref-bibr">26</a></sup></td></tr><tr><td><span class="sans-serif">Phospholipase A2, membrane-associated (PLA2)</span></td><td><span class="sans-serif">Promotion of cardiac repair following oxidative stress</span></td><td><span class="sans-serif">Calcium-independent PLA2 in ventricular cardiomyocytes localizes to mitochondria and peroxisomes and acts as a phospholipid repair enzyme following oxidative damage. Inhibition of phospholipase A2 is a mechanism underlying anthracycline cardiotoxicity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B27"></span><a href="javascript:;" reveal-id="ehac495-B27" data-open="ehac495-B27" class="link link-ref link-reveal xref-bibr">27</a>,<span class="xrefLink" id="jumplink-ehac495-B28"></span><a href="javascript:;" reveal-id="ehac495-B28" data-open="ehac495-B28" class="link link-ref link-reveal xref-bibr">28</a></sup></td></tr><tr><td><span class="sans-serif">Angiopoietin-related protein 4 (ANGPTL4)</span></td><td><span class="sans-serif">Reduction of oxidative stress and promotion of endothelial cell autophagy</span></td><td><span class="sans-serif">Inhibits lipoprotein lipase in cardiomyocytes. Prevents fatty acid-induced oxidative stress.</span><sup><span class="xrefLink" id="jumplink-ehac495-B29"></span><a href="javascript:;" reveal-id="ehac495-B29" data-open="ehac495-B29" class="link link-ref link-reveal xref-bibr">29</a></sup><span class="sans-serif">Preserves endothelial integrity by promotion of autophagy, thereby supporting myocardial function.</span><sup><span class="xrefLink" id="jumplink-ehac495-B30"></span><a href="javascript:;" reveal-id="ehac495-B30" data-open="ehac495-B30" class="link link-ref link-reveal xref-bibr">30</a></sup></td></tr><tr><td><span class="sans-serif">Insulin-like growth factor-binding protein 4 (IGFBP4)</span></td><td><span class="sans-serif">Reduction of oxidative stress and promotion of cardiac regenerative capacity</span></td><td><span class="sans-serif">Produces cardioprotection by minimizing the DNA injury produced by oxidative stress and promotes angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B31"></span><a href="javascript:;" reveal-id="ehac495-B31" data-open="ehac495-B31" class="link link-ref link-reveal xref-bibr">31</a></sup><span class="sans-serif">Enhances induction of cardiomyocytes from pluripotential stem cells by inhibition of the Wnt/β-catenin signalling, independent of its binding to IGF.</span><sup><span class="xrefLink" id="jumplink-ehac495-B32"></span><a href="javascript:;" reveal-id="ehac495-B32" data-open="ehac495-B32" class="link link-ref link-reveal xref-bibr">32</a></sup></td></tr><tr><td><span class="sans-serif">Protein-glutamine gamma-glutamyltransferase 2 (TGM2)</span></td><td><span class="sans-serif">Enhanced cardiac ATP synthesis, cardiac repair and regenerative capacity</span></td><td><span class="sans-serif">Enhanced fatty acid utilization and ATP synthesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B33"></span><a href="javascript:;" reveal-id="ehac495-B33" data-open="ehac495-B33" class="link link-ref link-reveal xref-bibr">33</a></sup><span class="sans-serif">Promotes cardiac repair and regenerative capacity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B34"></span><a href="javascript:;" reveal-id="ehac495-B34" data-open="ehac495-B34" class="link link-ref link-reveal xref-bibr">34</a></sup></td></tr><tr><td><span class="sans-serif">Mitochondrial creatine kinase, U-type (uMtCK)</span></td><td><span class="sans-serif">Support of cardiac energy metabolism</span></td><td><span class="sans-serif">Mediates the transfer of high energy phosphate from mitochondria to cytosol. Compensatory increase following oxidative stress has cardioprotective effects.</span><sup><span class="xrefLink" id="jumplink-ehac495-B35 ehac495-B36 ehac495-B37"></span><a href="javascript:;" reveal-id="ehac495-B35 ehac495-B36 ehac495-B37" data-open="ehac495-B35 ehac495-B36 ehac495-B37" class="link link-ref link-reveal xref-bibr">35–37</a></sup></td></tr><tr><td><span class="sans-serif">Connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed family member 5 (CCN5)</span></td><td><span class="sans-serif">Inhibition of cardiac fibrosis</span></td><td><span class="sans-serif">Inhibits cardiac hypertrophy. Interferes with endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, thereby reducing cardiac fibrosis. Prevents structural and electrical remodelling. Knockout leads to cardiomyopathy.</span><sup><span class="xrefLink" id="jumplink-ehac495-B38"></span><a href="javascript:;" reveal-id="ehac495-B38" data-open="ehac495-B38" class="link link-ref link-reveal xref-bibr">38</a>,<span class="xrefLink" id="jumplink-ehac495-B39"></span><a href="javascript:;" reveal-id="ehac495-B39" data-open="ehac495-B39" class="link link-ref link-reveal xref-bibr">39</a></sup></td></tr><tr><td><span class="sans-serif">Adipocyte fatty acid-binding protein 4 (AFABP4)</span></td><td><span class="sans-serif">Suppression of cardiac contractility</span></td><td><span class="sans-serif">Lipid binding protein that reduces fatty acid uptake by myocardium, thus suppresses cardiac contractility.</span><sup><span class="xrefLink" id="jumplink-ehac495-B40"></span><a href="javascript:;" reveal-id="ehac495-B40" data-open="ehac495-B40" class="link link-ref link-reveal xref-bibr">40</a>,<span class="xrefLink" id="jumplink-ehac495-B41"></span><a href="javascript:;" reveal-id="ehac495-B41" data-open="ehac495-B41" class="link link-ref link-reveal xref-bibr">41</a></sup><span class="sans-serif">May act as indicator of increased sirtuin-1 signalling and autophagic flux</span>.<sup><span class="xrefLink" id="jumplink-ehac495-B42"></span><a href="javascript:;" reveal-id="ehac495-B42" data-open="ehac495-B42" class="link link-ref link-reveal xref-bibr">42</a></sup></td></tr><tr><td><span class="sans-serif">Retinoic acid receptor responder protein 2 (Rarres2, chemerin)</span></td><td><span class="sans-serif">Promotion of cardiac hypertrophy, apoptosis, and angiogenesis</span></td><td><span class="sans-serif">Adipokine that induces cardiomyocyte hypertrophy, apoptosis, and angiogenesis.</span><sup><span class="xrefLink" id="jumplink-ehac495-B43"></span><a href="javascript:;" reveal-id="ehac495-B43" data-open="ehac495-B43" class="link link-ref link-reveal xref-bibr">43</a>,<span class="xrefLink" id="jumplink-ehac495-B44"></span><a href="javascript:;" reveal-id="ehac495-B44" data-open="ehac495-B44" class="link link-ref link-reveal xref-bibr">44</a></sup><span class="sans-serif">May act as biomarker of renal function, being inversely related to glomerular filtration rate.</span><sup><span class="xrefLink" id="jumplink-ehac495-B45"></span><a href="javascript:;" reveal-id="ehac495-B45" data-open="ehac495-B45" class="link link-ref link-reveal xref-bibr">45</a></sup></td></tr><tr><td colspan="3"><span class="sans-serif"><strong>Proteins with effects on the kidneys</strong></span></td></tr><tr><td><span class="sans-serif">Carbonic anhydrase 2 (CA2)</span></td><td><span class="sans-serif">Renal tubular sodium, bicarbonate, and water homeostasis</span></td><td><span class="sans-serif">Binds to and enhances the activity of NHE3 in the proximal renal tubule.</span><sup><span class="xrefLink" id="jumplink-ehac495-B46"></span><a href="javascript:;" reveal-id="ehac495-B46" data-open="ehac495-B46" class="link link-ref link-reveal xref-bibr">46</a></sup><span class="sans-serif">May offset increases in urinary bicarbonate and water resulting from SGLT2 inhibition.</span></td></tr><tr><td><span class="sans-serif">Guanylin (GUCA)</span></td><td><span class="sans-serif">Renal tubular sodium transport</span></td><td><span class="sans-serif">After the dietary salt load, guanylin and uroguanylin promote natriuresis by inhibiting NHE3 in proximal tubule</span><sup><span class="xrefLink" id="jumplink-ehac495-B47"></span><a href="javascript:;" reveal-id="ehac495-B47" data-open="ehac495-B47" class="link link-ref link-reveal xref-bibr">47</a>,<span class="xrefLink" id="jumplink-ehac495-B48"></span><a href="javascript:;" reveal-id="ehac495-B48" data-open="ehac495-B48" class="link link-ref link-reveal xref-bibr">48</a></sup></td></tr><tr><td><span class="sans-serif">Uromodulin (UMOD)</span></td><td><span class="sans-serif">Renal tubular sodium transport and muting of renal inflammation</span></td><td><span class="sans-serif">Promotes sodium reabsorption in the thick ascending limb of the loop of Henle.</span><sup><span class="xrefLink" id="jumplink-ehac495-B49"></span><a href="javascript:;" reveal-id="ehac495-B49" data-open="ehac495-B49" class="link link-ref link-reveal xref-bibr">49</a>,<span class="xrefLink" id="jumplink-ehac495-B50"></span><a href="javascript:;" reveal-id="ehac495-B50" data-open="ehac495-B50" class="link link-ref link-reveal xref-bibr">50</a></sup><span class="sans-serif">Acts as a trap for proinflammatory renal cytokines; loss-of-function mutations lead to chronic kidney disease.</span><sup><span class="xrefLink" id="jumplink-ehac495-B51"></span><a href="javascript:;" reveal-id="ehac495-B51" data-open="ehac495-B51" class="link link-ref link-reveal xref-bibr">51</a></sup></td></tr><tr><td><span class="sans-serif">Kidney injury molecule-1 (KIM-1)</span></td><td><span class="sans-serif">Promotion of renal proximal tubular injury, inflammation, and fibrosis</span></td><td><span class="sans-serif">Mediates renal tubular cell injury and apoptosis and promotes tubulointerstitial inflammation and fibrosis</span><sup><span class="xrefLink" id="jumplink-ehac495-B52 ehac495-B53 ehac495-B54"></span><a href="javascript:;" reveal-id="ehac495-B52 ehac495-B53 ehac495-B54" data-open="ehac495-B52 ehac495-B53 ehac495-B54" class="link link-ref link-reveal xref-bibr">52–54</a></sup></td></tr><tr><td><span class="sans-serif">Epithelial cell adhesion molecule (EpCAM)</span></td><td><span class="sans-serif">Promotion of renal tubular integrity and regeneration</span></td><td><span class="sans-serif">Promotes adhesion and polarity of renal tubular cells. EpCAM is suppressed by nephrotoxic agents and is enhanced during renal tubular regeneration</span><sup><span class="xrefLink" id="jumplink-ehac495-B55"></span><a href="javascript:;" reveal-id="ehac495-B55" data-open="ehac495-B55" class="link link-ref link-reveal xref-bibr">55</a>,<span class="xrefLink" id="jumplink-ehac495-B56"></span><a href="javascript:;" reveal-id="ehac495-B56" data-open="ehac495-B56" class="link link-ref link-reveal xref-bibr">56</a></sup></td></tr><tr><td><span class="sans-serif">Thymosin beta-10 (TMSB10)</span></td><td><span class="sans-serif">Promotion of renal tubular integrity and regeneration</span></td><td><span class="sans-serif">Plays important role in organization of cytoskeleton, thus promoting adhesion and polarity of renal parenchymal cells</span><sup><span class="xrefLink" id="jumplink-ehac495-B57"></span><a href="javascript:;" reveal-id="ehac495-B57" data-open="ehac495-B57" class="link link-ref link-reveal xref-bibr">57</a>,<span class="xrefLink" id="jumplink-ehac495-B58"></span><a href="javascript:;" reveal-id="ehac495-B58" data-open="ehac495-B58" class="link link-ref link-reveal xref-bibr">58</a></sup></td></tr><tr><td><span class="sans-serif">Beta-Ala-His dipeptidase (carnosinase 1, CNDP1)</span></td><td><span class="sans-serif">Degradation of nephroprotective carnosine</span></td><td><span class="sans-serif">Carnosine protects against the development of nephropathy, and gain-of-function mutations of carnosinase-1 cause carnosine depletion and increase risk of chronic kidney disease.</span><sup><span class="xrefLink" id="jumplink-ehac495-B59"></span><a href="javascript:;" reveal-id="ehac495-B59" data-open="ehac495-B59" class="link link-ref link-reveal xref-bibr">59</a></sup></td></tr><tr><td><span class="sans-serif">Angiopoietin-like protein 2 (ANGPTL2)</span></td><td><span class="sans-serif">Promotes renal inflammation and fibrosis</span></td><td><span class="sans-serif">Expressed in endothelial cells. Promotes oxidative stress, inflammation and fibrosis in the kidney and heart.</span><sup><span class="xrefLink" id="jumplink-ehac495-B60"></span><a href="javascript:;" reveal-id="ehac495-B60" data-open="ehac495-B60" class="link link-ref link-reveal xref-bibr">60</a>,<span class="xrefLink" id="jumplink-ehac495-B61"></span><a href="javascript:;" reveal-id="ehac495-B61" data-open="ehac495-B61" class="link link-ref link-reveal xref-bibr">61</a></sup><span class="sans-serif">May act as a marker of increased HIF-1</span>α <span class="sans-serif">activity.</span><sup><span class="xrefLink" id="jumplink-ehac495-B62"></span><a href="javascript:;" reveal-id="ehac495-B62" data-open="ehac495-B62" class="link link-ref link-reveal xref-bibr">62</a></sup></td></tr><tr><td colspan="3"><span class="sans-serif"><strong>Proteins With Effects Other Than on the Heart and Kidneys</strong></span></td></tr><tr><td><span class="sans-serif">Promotilin (MLN)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Prohormone for motilin, which promotes gastrointestinal motility. Produces relaxation of vascular smooth muscle, leading to systemic vasodilatation</span></td></tr><tr><td><span class="sans-serif">Serine proteases inhibitor Kazal-type 1 (SPINK1)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Inhibits trypsin with proposed role in the pathogenesis of pancreatitis. May be biomarker of renal function, since it increases in proportion to decreases in glomerular filtration rate</span></td></tr><tr><td><span class="sans-serif">C–C motif chemokine 18 (CCL18)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in lung, antigen-presenting dendritic cells and M2 macrophages and is chemoattractant for</span><br /><span class="sans-serif">T cells and lymphocytes</span></td></tr><tr><td><span class="sans-serif">C–C motif chemokine 27 (CCL 27)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in skin and mediates homing of memory T lymphocytes to cutaneous sites</span></td></tr><tr><td><span class="sans-serif">Cystatin-F (CYTF, CST6)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Inhibits cathepsin C-directed protease. Expressed in immune cells and causes down-regulation of killing efficiency of cytotoxic T lymphocytes</span></td></tr><tr><td><span class="sans-serif">Scavenger receptor cysteine-rich domain-containing group B protein (SRCR)</span></td><td><span class="sans-serif">No known action in the heart or kidney</span></td><td><span class="sans-serif">Expressed in epithelial cells and plays a role in mucosal immunity and innate defence</span></td></tr></tbody></table></div><div class="table-wrap-foot"><span id="fn-tblfn2"></span><div content-id="tblfn2" class="footnote"><span class="fn"><p class="chapter-para">RBP2 has effects on the heart and kidneys, but to avoid duplication, <em>t</em> is described only in the section on the heart.</p></span></div><span id="fn-tblfn3"></span><div content-id="tblfn3" class="footnote"><span class="fn"><p class="chapter-para">AMPK, adenosine monophosphate-activated protein kinase; ATP, adenosine triphosphate; IGF1, insulin-like growth factor 1; NAD+, nicotinamide adenine dinucleotide; NHE3, sodium–hydrogen exchanger isoform 3; Wnt, Wingless-related integration site glycoprotein; HIF-1α, hypoxia-inducible factor-1α.</p></span></div></div></div></div><p class="chapter-para">Fourteen proteins have established effects in the heart, and of these, the most common effect was the promotion of autophagic flux (five proteins), which was particularly characteristic of the three cardiac-acting proteins that had the largest effect size (IGFBP1, TfR1, and EPO), <em><span class="xrefLink" id="jumplink-ehac495-T1"></span><a href="javascript:;" reveal-id="ehac495-T1" data-open="ehac495-T1" class="link link-reveal link-table xref-fig">Table 1</a></em>.<sup><span class="xrefLink" id="jumplink-ehac495-B10"></span><a href="javascript:;" reveal-id="ehac495-B10" data-open="ehac495-B10" class="link link-ref link-reveal xref-bibr">10</a>,<span class="xrefLink" id="jumplink-ehac495-B13"></span><a href="javascript:;" reveal-id="ehac495-B13" data-open="ehac495-B13" class="link link-ref link-reveal xref-bibr">13</a>,<span class="xrefLink" id="jumplink-ehac495-B15"></span><a href="javascript:;" reveal-id="ehac495-B15" data-open="ehac495-B15" class="link link-ref link-reveal xref-bibr">15</a></sup> Most of the other 11 proteins have been shown to reduce oxidative stress or its consequences, inhibit apoptosis, inflammation and fibrosis, and enhance the energy, repair and regenerative capacity of the heart (<em><span class="xrefLink" id="jumplink-ehac495-T2"></span><a href="javascript:;" reveal-id="ehac495-T2" data-open="ehac495-T2" class="link link-reveal link-table xref-fig">Table 2</a></em> and <em><span class="xrefLink" id="jumplink-ehac495-F2"></span><a href="javascript:;" data-modal-source-id="ehac495-F2" class="link xref-fig">Figure 2</a></em>).</p> <a id="388939884" scrollto-destination="388939884"></a> <div data-id="ehac495-f2" data-content-id="ehac495-f2" class="fig fig-section js-fig-section" swap-content-for-modal="true"><div class="graphic-wrap"><img class="content-image" src="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/m_ehac495f2.jpeg?Expires=1735388495&Signature=BapOSgkNlmPmx-bIQQTJPIk~pkxfJxN5zMok2a9vPGg1jltswgqtfMlvL823bpPGTipik1kPBWXvfxng-pbL0Rlvzr9WWra71JM3fEAz7XmFE58eEt0a1ElQYt-d4e0Fj1iv0ysMklXnwksiq6tGV25sjMnKS8VmhfHd80daLGQHCKfVYSWTh7Q1~0Se3XEsLT~kNRspmqmIgAHF-e1I6Uwinb5FRjPhcXnmowwBdnN81xAlt4n8qBDBia6YKqiIy4AOJJJhZgaALgs0F4Xl2Y3SDdxEEL7esfn0myN9rw5tIUyc4tMj5nJEh~uVtfuB5ienoAdXQkQ~H0sBVYH1NA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA" alt="Favourable biological and cellular actions of differentially expressed proteins in the heart and kidney. Empagliflozin had the largest treatment effect on proteins shown in a larger font and in italics. RBP2 has both cardioprotective and nephroprotective effects. IGFBP1, insulin-like growth factor-binding protein 1; TfR1, transferrin receptor protein 1; EPO, erythropoietin; TGM2, protein-glutamine gamma-glutamyltransferase 2; TMSB10, thymosin beta-10; uMtCK, mitochondrial creatine kinase U-type; IGFBP4, insulin-like growth factor-binding protein 4; EpCAM, epithelial cell adhesion molecule; PLA2, phospholipase A2; ANGPTL4, angiopoietin-related protein 4; RBP2, retinol-binding protein 2; CCN5, CCN family member 5; CCL16, C–C motif chemokine 16; NPDC1, neural proliferation differentiation and control protein 1; FST, follistatin; Mdk, midkine; GUCA, guanylin." data-path-from-xml="ehac495f2.tif" /><div class="graphic-bottom"><div class="label fig-label" id="label-388939884">Figure 2</div><div class="caption fig-caption"><p class="chapter-para">Favourable biological and cellular actions of differentially expressed proteins in the heart and kidney. Empagliflozin had the largest treatment effect on proteins shown in a larger font and in italics. RBP2 has both cardioprotective and nephroprotective effects. IGFBP1, insulin-like growth factor-binding protein 1; TfR1, transferrin receptor protein 1; EPO, erythropoietin; TGM2, protein-glutamine gamma-glutamyltransferase 2; TMSB10, thymosin beta-10; uMtCK, mitochondrial creatine kinase U-type; IGFBP4, insulin-like growth factor-binding protein 4; EpCAM, epithelial cell adhesion molecule; PLA2, phospholipase A2; ANGPTL4, angiopoietin-related protein 4; RBP2, retinol-binding protein 2; CCN5, CCN family member 5; CCL16, C–C motif chemokine 16; NPDC1, neural proliferation differentiation and control protein 1; FST, follistatin; Mdk, midkine; GUCA, guanylin.</p></div><div class="ajax-articleAbstract-exclude-regex fig-orig original-slide figure-button-wrap"><a class="fig-view-orig js-view-large at-figureViewLarge openInAnotherWindow" role="button" aria-describedby="label-388939884" href="/view-large/figure/388939884/ehac495f2.tif" data-path-from-xml="ehac495f2.tif" target="_blank">Open in new tab</a><a class="download-slide" role="button" aria-describedby="label-388939884" data-section="388939884" href="/DownloadFile/DownloadImage.aspx?image=https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495f2.jpeg?Expires=1735388495&Signature=0kRK5IMEMktd1AwIg63dv5-nk9FmTKXVcnVDJ2JPd61LWaQRRrJR5gtsBrkUPDjoIZ6~t9tjfrAU1TJfVbSPDRik79NSRqzTrwNTddpEUmEnEPzCYF4D38lPmXaNjydPuLLc8BsuAMPk7cO~0qloO~bEOeDgGZP5-geoXcPMoygyCXsK08g-x~uSWUOuBOLlstJKcMMhcMhzCwXDpV14BRA94VQGsdR3QuT8utEVQyIOwtTkHH7Zh0Re0nFmeEDturBobXSaJ4N2Q7YgLDSoUll9rrKs8rEL3iZGe-yTY4qOv-HAjqMbv5pcTJmUw-KDz2397NREI5QyxwNJpl04Kw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA&sec=388939884&ar=6676779&xsltPath=~/UI/app/XSLT&imagename=&siteId=5375" data-path-from-xml="ehac495f2.tif">Download slide</a></div></div></div></div><p class="chapter-para">Nine proteins have established effects in the kidney (<em><span class="xrefLink" id="jumplink-ehac495-T2"></span><a href="javascript:;" reveal-id="ehac495-T2" data-open="ehac495-T2" class="link link-reveal link-table xref-fig">Table 2</a></em>), and of these, three proteins (CA2, guanylin, and uromodulin) have actions on sodium transport in the renal tubules.<sup><span class="xrefLink" id="jumplink-ehac495-B46"></span><a href="javascript:;" reveal-id="ehac495-B46" data-open="ehac495-B46" class="link link-ref link-reveal xref-bibr">46</a>,<span class="xrefLink" id="jumplink-ehac495-B47"></span><a href="javascript:;" reveal-id="ehac495-B47" data-open="ehac495-B47" class="link link-ref link-reveal xref-bibr">47</a>,<span class="xrefLink" id="jumplink-ehac495-B50"></span><a href="javascript:;" reveal-id="ehac495-B50" data-open="ehac495-B50" class="link link-ref link-reveal xref-bibr">50</a></sup> Two proteins have been shown to inhibit renal injury, inflammation, and fibrosis (uromodulin and KIM-1),<sup><span class="xrefLink" id="jumplink-ehac495-B51"></span><a href="javascript:;" reveal-id="ehac495-B51" data-open="ehac495-B51" class="link link-ref link-reveal xref-bibr">51</a>,<span class="xrefLink" id="jumplink-ehac495-B54"></span><a href="javascript:;" reveal-id="ehac495-B54" data-open="ehac495-B54" class="link link-ref link-reveal xref-bibr">54</a></sup> and three proteins play a role in promoting renal autophagy, tubular integrity and regeneration [retinol-binding protein 2 (RBP2), TSMB10 and epithelial cell adhesion molecule (EpCAM)], <em><span class="xrefLink" id="jumplink-ehac495-F2"></span><a href="javascript:;" data-modal-source-id="ehac495-F2" class="link xref-fig">Figure 2</a></em> and <em><span class="xrefLink" id="jumplink-ehac495-T2"></span><a href="javascript:;" reveal-id="ehac495-T2" data-open="ehac495-T2" class="link link-reveal link-table xref-fig">Table 2</a></em>.<sup><span class="xrefLink" id="jumplink-ehac495-B24"></span><a href="javascript:;" reveal-id="ehac495-B24" data-open="ehac495-B24" class="link link-ref link-reveal xref-bibr">24</a>,<span class="xrefLink" id="jumplink-ehac495-B56"></span><a href="javascript:;" reveal-id="ehac495-B56" data-open="ehac495-B56" class="link link-ref link-reveal xref-bibr">56</a>,<span class="xrefLink" id="jumplink-ehac495-B57"></span><a href="javascript:;" reveal-id="ehac495-B57" data-open="ehac495-B57" class="link link-ref link-reveal xref-bibr">57</a></sup></p> <h2 scrollto-destination=388939886 id="388939886" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s3>Discussion</h2> <p class="chapter-para">Our proteomics analysis of blood samples taken from participants pooled from the EMPEROR-Reduced and EMPEROR-Preserved trials indicate that circulating levels of approximately 30 proteins changed meaningfully during SGLT2 inhibition with empagliflozin (<em><span class="xrefLink" id="jumplink-ehac495ga1"></span><a href="javascript:;" data-modal-source-id="ehac495ga1" class="link xref-fig">Structured Graphical Abstract</a></em>). Concentrations of these proteins changed by at least 10%, and they did so with substantial consistency, yielding results that were highly statistically significant, even after major adjustment for multiplicity of testing. Our thresholds for identifying differentially expressed proteins were similar to or more stringent than those used in other cardiovascular proteomics analyses; we used a false discovery rate of <1%, rather than the <5% that has been commonly used in other studies.<sup><span class="xrefLink" id="jumplink-ehac495-B63"></span><a href="javascript:;" reveal-id="ehac495-B63" data-open="ehac495-B63" class="link link-ref link-reveal xref-bibr">63</a></sup> Importantly, the changes in the circulating levels of most differentially expressed proteins were not related to changes in renal clearance than may have been produced by empagliflozin as a result of its action to reduce intraglomerular filtration pressures, since our results did not meaningfully change following adjustment for changes in glomerular filtration rate. It should be understood that most of the proteins that we assessed act intracellularly, and it is plausible that changes in circulating levels parallel changes in the intracellular concentration of these proteins with subsequent release from the cytosol. However, the magnitude of this release does not necessarily reflect the intracellular expression or activation of these proteins, whose stochiometric relationships may not be linear. Furthermore, our proteomics analyses cannot identify the organ sources of this protein release.</p><p class="chapter-para">In experimental studies, SGLT2 inhibitors have been shown to exert cardioprotective and nephroprotective effects by promoting autophagic flux and mitigating apoptosis, muting oxidative and other cellular stresses, inhibiting proinflammatory and profibrotic pathways, and enhancing cellular energy stores and metabolism.<sup><span class="xrefLink" id="jumplink-ehac495-B3"></span><a href="javascript:;" reveal-id="ehac495-B3" data-open="ehac495-B3" class="link link-ref link-reveal xref-bibr">3</a>,<span class="xrefLink" id="jumplink-ehac495-B64 ehac495-B65 ehac495-B66 ehac495-B67 ehac495-B68"></span><a href="javascript:;" reveal-id="ehac495-B64 ehac495-B65 ehac495-B66 ehac495-B67 ehac495-B68" data-open="ehac495-B64 ehac495-B65 ehac495-B66 ehac495-B67 ehac495-B68" class="link link-ref link-reveal xref-bibr">64–68</a></sup> It is therefore noteworthy that most of the 33 differentially expressed proteins identified in our proteomics analyses have been shown to exert favourable effects on the heart and kidney in hypothesis-driven experimental studies performed in animal models of cardiac and renal injury (<em><span class="xrefLink" id="jumplink-ehac495-T2"></span><a href="javascript:;" reveal-id="ehac495-T2" data-open="ehac495-T2" class="link link-reveal link-table xref-fig">Table 2</a></em>). Of particular note, six proteins have been shown to promote autophagic flux in the heart, kidney or endothelium, i.e. IGFBP1, TfR1, EPO, follistatin, angiopoietin-related protein 4 (ANGPTL4), and RBP2.<sup><span class="xrefLink" id="jumplink-ehac495-B10"></span><a href="javascript:;" reveal-id="ehac495-B10" data-open="ehac495-B10" class="link link-ref link-reveal xref-bibr">10</a>,<span class="xrefLink" id="jumplink-ehac495-B11"></span><a href="javascript:;" reveal-id="ehac495-B11" data-open="ehac495-B11" class="link link-ref link-reveal xref-bibr">11</a>,<span class="xrefLink" id="jumplink-ehac495-B13"></span><a href="javascript:;" reveal-id="ehac495-B13" data-open="ehac495-B13" class="link link-ref link-reveal xref-bibr">13</a>,<span class="xrefLink" id="jumplink-ehac495-B15"></span><a href="javascript:;" reveal-id="ehac495-B15" data-open="ehac495-B15" class="link link-ref link-reveal xref-bibr">15</a>,<span class="xrefLink" id="jumplink-ehac495-B19"></span><a href="javascript:;" reveal-id="ehac495-B19" data-open="ehac495-B19" class="link link-ref link-reveal xref-bibr">19</a>,<span class="xrefLink" id="jumplink-ehac495-B24"></span><a href="javascript:;" reveal-id="ehac495-B24" data-open="ehac495-B24" class="link link-ref link-reveal xref-bibr">24</a>,<span class="xrefLink" id="jumplink-ehac495-B30"></span><a href="javascript:;" reveal-id="ehac495-B30" data-open="ehac495-B30" class="link link-ref link-reveal xref-bibr">30</a></sup></p><p class="chapter-para">Five proteins have been shown to reduce the levels or consequences of oxidative stress and improve mitochondrial health in the myocardium (TfR1, phospholipase A2 (PLA2), ANGLPTL4, IGFBP4, and uMtCK).<sup><span class="xrefLink" id="jumplink-ehac495-B13"></span><a href="javascript:;" reveal-id="ehac495-B13" data-open="ehac495-B13" class="link link-ref link-reveal xref-bibr">13</a>,<span class="xrefLink" id="jumplink-ehac495-B28"></span><a href="javascript:;" reveal-id="ehac495-B28" data-open="ehac495-B28" class="link link-ref link-reveal xref-bibr">28</a>,<span class="xrefLink" id="jumplink-ehac495-B29"></span><a href="javascript:;" reveal-id="ehac495-B29" data-open="ehac495-B29" class="link link-ref link-reveal xref-bibr">29</a>,<span class="xrefLink" id="jumplink-ehac495-B31"></span><a href="javascript:;" reveal-id="ehac495-B31" data-open="ehac495-B31" class="link link-ref link-reveal xref-bibr">31</a>,<span class="xrefLink" id="jumplink-ehac495-B36"></span><a href="javascript:;" reveal-id="ehac495-B36" data-open="ehac495-B36" class="link link-ref link-reveal xref-bibr">36</a></sup> Four proteins have been reported to enhance energy metabolism, cardiac repair or the renewal of cardiomyocytes (RBP2, IGFBP4, TGM2, and uMtCK).<sup><span class="xrefLink" id="jumplink-ehac495-B23"></span><a href="javascript:;" reveal-id="ehac495-B23" data-open="ehac495-B23" class="link link-ref link-reveal xref-bibr">23</a>,<span class="xrefLink" id="jumplink-ehac495-B32 ehac495-B33 ehac495-B34 ehac495-B35"></span><a href="javascript:;" reveal-id="ehac495-B32 ehac495-B33 ehac495-B34 ehac495-B35" data-open="ehac495-B32 ehac495-B33 ehac495-B34 ehac495-B35" class="link link-ref link-reveal xref-bibr">32–35</a></sup> As a result of these and other actions, many of the differentially expressed proteins have favourable effects to retard maladaptive ventricular hypertrophy or remodelling, <em><span class="xrefLink" id="jumplink-ehac495-T2"></span><a href="javascript:;" reveal-id="ehac495-T2" data-open="ehac495-T2" class="link link-reveal link-table xref-fig">Table 2</a></em>. In addition, two proteins have demonstrated effects to mitigate renal injury and inflammation (uromodulin and KIM-1),<sup><span class="xrefLink" id="jumplink-ehac495-B49"></span><a href="javascript:;" reveal-id="ehac495-B49" data-open="ehac495-B49" class="link link-ref link-reveal xref-bibr">49</a>,<span class="xrefLink" id="jumplink-ehac495-B52"></span><a href="javascript:;" reveal-id="ehac495-B52" data-open="ehac495-B52" class="link link-ref link-reveal xref-bibr">52</a></sup> three proteins have been shown to promote renal autophagy or enhance the integrity or regeneration of renal tubular cells (RBP2, TSMB10, and EpCAM),<sup><span class="xrefLink" id="jumplink-ehac495-B55"></span><a href="javascript:;" reveal-id="ehac495-B55" data-open="ehac495-B55" class="link link-ref link-reveal xref-bibr">55</a>,<span class="xrefLink" id="jumplink-ehac495-B57"></span><a href="javascript:;" reveal-id="ehac495-B57" data-open="ehac495-B57" class="link link-ref link-reveal xref-bibr">57</a></sup> and three proteins (CA2, guanylin, and uromodulin) play a role in renal tubular sodium transport.<sup><span class="xrefLink" id="jumplink-ehac495-B47"></span><a href="javascript:;" reveal-id="ehac495-B47" data-open="ehac495-B47" class="link link-ref link-reveal xref-bibr">47</a>,<span class="xrefLink" id="jumplink-ehac495-B49"></span><a href="javascript:;" reveal-id="ehac495-B49" data-open="ehac495-B49" class="link link-ref link-reveal xref-bibr">49</a></sup> Therefore, our proteomics analyses suggest that the pathways that are influenced by SGLT2 inhibitors in patients with heart failure are similar to those influenced by these drugs in animal models of cardiac or renal stress.<sup><span class="xrefLink" id="jumplink-ehac495-B64 ehac495-B65 ehac495-B66 ehac495-B67 ehac495-B68 ehac495-B69"></span><a href="javascript:;" reveal-id="ehac495-B64 ehac495-B65 ehac495-B66 ehac495-B67 ehac495-B68 ehac495-B69" data-open="ehac495-B64 ehac495-B65 ehac495-B66 ehac495-B67 ehac495-B68 ehac495-B69" class="link link-ref link-reveal xref-bibr">64–69</a></sup></p><p class="chapter-para">Importantly, our conclusions remained unaltered even when we focused on proteins with the most marked changes, <em><span class="xrefLink" id="jumplink-ehac495-F1"></span><a href="javascript:;" data-modal-source-id="ehac495-F1" class="link xref-fig">Figure 1</a></em>. The protein that showed the most striking increase was IGFBP1, which binds to insulin-like growth factor 1 (IGF1) to limit its activity. IGF1 has demonstrable deleterious effects on the heart to suppress autophagy, and its upregulation promotes the development of cardiomyopathy.<sup><span class="xrefLink" id="jumplink-ehac495-B10"></span><a href="javascript:;" reveal-id="ehac495-B10" data-open="ehac495-B10" class="link link-ref link-reveal xref-bibr">10</a></sup> The protein that showed the second largest treatment effect in the current study was TfR1, which is required for iron transport into cardiomyocytes to prevent contractile dysfunction,<sup><span class="xrefLink" id="jumplink-ehac495-B70"></span><a href="javascript:;" reveal-id="ehac495-B70" data-open="ehac495-B70" class="link link-ref link-reveal xref-bibr">70</a></sup> but it also enhances nutrient deprivation signalling.<sup><span class="xrefLink" id="jumplink-ehac495-B14"></span><a href="javascript:;" reveal-id="ehac495-B14" data-open="ehac495-B14" class="link link-ref link-reveal xref-bibr">14</a></sup> Knockout of TfR1 leads to mitochondrial derangements, suppression of autophagy and the development of cardiomyopathy.<sup><span class="xrefLink" id="jumplink-ehac495-B13"></span><a href="javascript:;" reveal-id="ehac495-B13" data-open="ehac495-B13" class="link link-ref link-reveal xref-bibr">13</a></sup> The third most differentially expressed protein related to heart function was EPO, which is classically known as the principal stimulus to red blood cell production. However, EPO also exerts direct effects on the heart (independent of its actions on erythrocytosis) to promote autophagy, prevent adverse ventricular remodelling, and mute proinflammatory and profibrotic signalling in the myocardium.<sup><span class="xrefLink" id="jumplink-ehac495-B15 ehac495-B16 ehac495-B17"></span><a href="javascript:;" reveal-id="ehac495-B15 ehac495-B16 ehac495-B17" data-open="ehac495-B15 ehac495-B16 ehac495-B17" class="link link-ref link-reveal xref-bibr">15–17</a></sup> Interestingly, all three proteins are functionally related to the increases in haemoglobin seen in clinical trials with SGLT2 inhibitors, a physiological change that is the most important statistical mediator of the benefit of SGLT2 inhibitors to reduce heart failure and major adverse renal events.<sup><span class="xrefLink" id="jumplink-ehac495-B5"></span><a href="javascript:;" reveal-id="ehac495-B5" data-open="ehac495-B5" class="link link-ref link-reveal xref-bibr">5</a>,<span class="xrefLink" id="jumplink-ehac495-B6"></span><a href="javascript:;" reveal-id="ehac495-B6" data-open="ehac495-B6" class="link link-ref link-reveal xref-bibr">6</a></sup> Specifically, IGFBP1 promotes the stability of hypoxic inducible factor 1-α,<sup><span class="xrefLink" id="jumplink-ehac495-B11"></span><a href="javascript:;" reveal-id="ehac495-B11" data-open="ehac495-B11" class="link link-ref link-reveal xref-bibr">11</a></sup> an important endogenous stimulus to the production or erythropoietin, while TfR1 ensures the adequacy of intracellular levels of iron in erythrocytes.<sup><span class="xrefLink" id="jumplink-ehac495-B71"></span><a href="javascript:;" reveal-id="ehac495-B71" data-open="ehac495-B71" class="link link-ref link-reveal xref-bibr">71</a></sup> Interestingly, increased levels of ANGPTL2 may also serve as an indicator of increased hypoxic inducible factor 1-α signalling.<sup><span class="xrefLink" id="jumplink-ehac495-B62"></span><a href="javascript:;" reveal-id="ehac495-B62" data-open="ehac495-B62" class="link link-ref link-reveal xref-bibr">62</a></sup></p><p class="chapter-para">Three prior studies have reported the results of proteomics analyses before and after SGLT2 inhibition, but the three studies each evaluated fewer than 80 patients, <10% of the patients in the current EMPEROR proteomics substudy.<sup><span class="xrefLink" id="jumplink-ehac495-B63"></span><a href="javascript:;" reveal-id="ehac495-B63" data-open="ehac495-B63" class="link link-ref link-reveal xref-bibr">63</a>,<span class="xrefLink" id="jumplink-ehac495-B72"></span><a href="javascript:;" reveal-id="ehac495-B72" data-open="ehac495-B72" class="link link-ref link-reveal xref-bibr">72</a>,<span class="xrefLink" id="jumplink-ehac495-B73"></span><a href="javascript:;" reveal-id="ehac495-B73" data-open="ehac495-B73" class="link link-ref link-reveal xref-bibr">73</a></sup> Of the three, the study most comparable to our analyses was carried out by Ferrannini <em>et al.</em>,<sup><span class="xrefLink" id="jumplink-ehac495-B63"></span><a href="javascript:;" reveal-id="ehac495-B63" data-open="ehac495-B63" class="link link-ref link-reveal xref-bibr">63</a></sup> although that study differed from ours in several important respects. First, Ferrannini <em>et al.</em> studied the effects of empagliflozin in patients with Type 2 diabetes, whereas we studied the effects of empagliflozin in patients with chronic heart failure. Ferrannini <em>et al</em> measured proteins using an aptamer-based assay, whereas we performed measurements using a PEA method. Ferrannini <em>et al.</em> performed measurements after only 4 weeks of treatment, whereas we carried out our assessments after 12 and 52 weeks of therapy. Despite these differences, it is noteworthy that Ferrannini <em>et al</em>. also observed that the proteins most prominently affected by SGLT2 inhibition were IGFBP1, TfR1, EPO and AFABP4, findings that are strikingly concordant with the major observations of the current proteomics analyses from the EMPEROR trials. Interestingly, IGFBP1, TfR1, EPO, and AFABP4 are all linked to increased activity of sirtuin-1, a nutrient deprivation sensor that promotes autophagy and is known to be increased by SGLT2 inhibitors in experimental studies and that appears to be essential to mediating their benefits.<sup><span class="xrefLink" id="jumplink-ehac495-B74"></span><a href="javascript:;" reveal-id="ehac495-B74" data-open="ehac495-B74" class="link link-ref link-reveal xref-bibr">74</a></sup> Experimentally, the effects of SGLT2 inhibitors to reduce cellular stress and attenuate apoptosis in cardiomyocytes are abolished when the actions of sirtuin-1 are inhibited.<sup><span class="xrefLink" id="jumplink-ehac495-B75"></span><a href="javascript:;" reveal-id="ehac495-B75" data-open="ehac495-B75" class="link link-ref link-reveal xref-bibr">75</a></sup> It is therefore noteworthy that sirtuin-1 directly stimulates the expression of both IGFBP1 and AFABP4,<sup><span class="xrefLink" id="jumplink-ehac495-B12"></span><a href="javascript:;" reveal-id="ehac495-B12" data-open="ehac495-B12" class="link link-ref link-reveal xref-bibr">12</a>,<span class="xrefLink" id="jumplink-ehac495-B42"></span><a href="javascript:;" reveal-id="ehac495-B42" data-open="ehac495-B42" class="link link-ref link-reveal xref-bibr">42</a></sup> TfR1 is required for sirtuin-1 synthesis,<sup><span class="xrefLink" id="jumplink-ehac495-B14"></span><a href="javascript:;" reveal-id="ehac495-B14" data-open="ehac495-B14" class="link link-ref link-reveal xref-bibr">14</a></sup> and sirtuin-1 can stimulate the production of EPO by an action on hypoxia-inducible factor 2-α.<sup><span class="xrefLink" id="jumplink-ehac495-B18"></span><a href="javascript:;" reveal-id="ehac495-B18" data-open="ehac495-B18" class="link link-ref link-reveal xref-bibr">18</a></sup></p><p class="chapter-para">Our proteomics findings are also consistent with the upregulation of proteins that have favourable effects on renal structure and function. Upregulation of RBP2 may enhance the ability of retinoic acid to prevent renal injury by promoting autophagic flux in renal parenchymal cells.<sup><span class="xrefLink" id="jumplink-ehac495-B24"></span><a href="javascript:;" reveal-id="ehac495-B24" data-open="ehac495-B24" class="link link-ref link-reveal xref-bibr">24</a></sup> Increases in circulating levels of TSAMB10 and EpCAM may be critical to the establishment of the adhesion and polarity of renal tubular cells, a critical step in their regeneration following injury.<sup><span class="xrefLink" id="jumplink-ehac495-B55 ehac495-B56 ehac495-B57 ehac495-B58"></span><a href="javascript:;" reveal-id="ehac495-B55 ehac495-B56 ehac495-B57 ehac495-B58" data-open="ehac495-B55 ehac495-B56 ehac495-B57 ehac495-B58" class="link link-ref link-reveal xref-bibr">55–58</a></sup> During long-term treatment, SGLT2 inhibition produced meaningful decreases in KIM-1, which mediates renal tubular cell injury and apoptosis and promotes tubulointerstitial inflammation and fibrosis.<sup><span class="xrefLink" id="jumplink-ehac495-B52 ehac495-B53 ehac495-B54"></span><a href="javascript:;" reveal-id="ehac495-B52 ehac495-B53 ehac495-B54" data-open="ehac495-B52 ehac495-B53 ehac495-B54" class="link link-ref link-reveal xref-bibr">52–54</a></sup> The concerted actions of these differentially increased proteins closely mimic the known effects of SGLT2 inhibitors to prevent renal injury, inflammation, and fibrosis in experimental studies of renal stress in animal models.<sup><span class="xrefLink" id="jumplink-ehac495-B64"></span><a href="javascript:;" reveal-id="ehac495-B64" data-open="ehac495-B64" class="link link-ref link-reveal xref-bibr">64</a></sup></p><p class="chapter-para">Interestingly, several of our differentially expressed proteins may represent a mechanism by which the kidney may compensate for the renal tubular actions of SGLT2 inhibitors. SGLT2 inhibitors interfere with sodium reabsorption in the proximal renal tubule through an action to inhibit both SGLT2 and sodium–hydrogen exchanger isoform 3 (NHE3).<sup><span class="xrefLink" id="jumplink-ehac495-B69"></span><a href="javascript:;" reveal-id="ehac495-B69" data-open="ehac495-B69" class="link link-ref link-reveal xref-bibr">69</a>,<span class="xrefLink" id="jumplink-ehac495-B76"></span><a href="javascript:;" reveal-id="ehac495-B76" data-open="ehac495-B76" class="link link-ref link-reveal xref-bibr">76</a></sup> Guanylin also acts in the proximal tubule to inhibit NHE3,<sup><span class="xrefLink" id="jumplink-ehac495-B47"></span><a href="javascript:;" reveal-id="ehac495-B47" data-open="ehac495-B47" class="link link-ref link-reveal xref-bibr">47</a></sup> but it is secreted following a dietary salt load;<sup><span class="xrefLink" id="jumplink-ehac495-B77"></span><a href="javascript:;" reveal-id="ehac495-B77" data-open="ehac495-B77" class="link link-ref link-reveal xref-bibr">77</a></sup> its action reinforces the effect of SGLT2 inhibitors to promote the urinary excretion of sodium and bicarbonate.<sup><span class="xrefLink" id="jumplink-ehac495-B76"></span><a href="javascript:;" reveal-id="ehac495-B76" data-open="ehac495-B76" class="link link-ref link-reveal xref-bibr">76</a>,<span class="xrefLink" id="jumplink-ehac495-B78"></span><a href="javascript:;" reveal-id="ehac495-B78" data-open="ehac495-B78" class="link link-ref link-reveal xref-bibr">78</a></sup> Yet, the observed increase in levels of CA2 may represent a compensatory mechanism to these effects. CA2 binds to NHE3 to increase its activity,<sup><span class="xrefLink" id="jumplink-ehac495-B46"></span><a href="javascript:;" reveal-id="ehac495-B46" data-open="ehac495-B46" class="link link-ref link-reveal xref-bibr">46</a></sup> and CA2 enhances the renal tubular adaptation to the increase in urinary bicarbonate that follows the action of SGLT2 inhibitors and guanylin to inhibit NHE3.<sup><span class="xrefLink" id="jumplink-ehac495-B79"></span><a href="javascript:;" reveal-id="ehac495-B79" data-open="ehac495-B79" class="link link-ref link-reveal xref-bibr">79</a></sup> In addition, CA2 acts to counter the increase in free water clearance that is seen when glycosuria is induced by SGLT2 inhibitors.<sup><span class="xrefLink" id="jumplink-ehac495-B80"></span><a href="javascript:;" reveal-id="ehac495-B80" data-open="ehac495-B80" class="link link-ref link-reveal xref-bibr">80</a></sup> Uromodulin can further counteract the natriuretic effect of SGLT2 inhibitors by enhancing sodium reabsorption more distally in the nephron.<sup><span class="xrefLink" id="jumplink-ehac495-B50"></span><a href="javascript:;" reveal-id="ehac495-B50" data-open="ehac495-B50" class="link link-ref link-reveal xref-bibr">50</a></sup> The activation of these counterregulatory mechanisms may explain why the initial natriuretic and osmotic diuretic response to SGLT2 inhibitors is not sustained.<sup><span class="xrefLink" id="jumplink-ehac495-B81 ehac495-B82 ehac495-B83"></span><a href="javascript:;" reveal-id="ehac495-B81 ehac495-B82 ehac495-B83" data-open="ehac495-B81 ehac495-B82 ehac495-B83" class="link link-ref link-reveal xref-bibr">81–83</a></sup> Accordingly, we observed no meaningful decrease in NT-proBNP in the current study, a finding consistent with our earlier observations based on a conventional ELISA assay.<sup><span class="xrefLink" id="jumplink-ehac495-B84"></span><a href="javascript:;" reveal-id="ehac495-B84" data-open="ehac495-B84" class="link link-ref link-reveal xref-bibr">84</a></sup></p><p class="chapter-para">Our findings should be considered in light of certain strengths and limitations. Our proteomic analyses examined >1200 proteins in blood collected from >1100 patients who participated in two placebo-controlled randomized trials. Therefore, our study represents the largest proteomic database to date on the effects of SGLT2 inhibitors. Despite this advantage, we had an insufficient number of patients in each trial to adequately examine potential differences in the effects of SGLT2 inhibitors between patients with a reduced and preserved ejection fraction, and we needed to pool our data across both trials to maximize statistical power. Another strength of the study is that we assessed changes at both 12 and 52 weeks, enabling us to show that the effects seen early in treatment were generally not meaningfully different during long-term therapy. Although we adjusted for changes in renal function that occurred during the first 12 weeks, we did not adjust for changes in concomitant medications, which have the potential to influence protein expression independent of the study medication; however, changes in background therapy during the first 12 weeks were modest.</p><p class="chapter-para">Most importantly, although our proximal extension assay has certain advantages over aptamer-based methods (which measure protein fragments), our Olink platform measured only a small fraction of the intracellular proteins that have been implicated in the action of SGLT2 inhibitors in experimental studies. Furthermore, we did not measure many of the proteins that Ferrannini <em>et al</em>.<sup><span class="xrefLink" id="jumplink-ehac495-B63"></span><a href="javascript:;" reveal-id="ehac495-B63" data-open="ehac495-B63" class="link link-ref link-reveal xref-bibr">63</a></sup> noted to be meaningfully changed by empagliflozin using aptamer-based methods (including growth differentiation factor 15 and ferritin). Most importantly, we did not directly measure any of the proteins that are involved in enhanced nutrient deprivation signalling and have been implicated in mediating the actions of SGLT2 inhibitors on cardiomyocytes and renal tubular cells (e.g. sirtuin-1, proliferator-activated receptor gamma coactivator 1-α, phosphorylated mammalian target of rapamycin, and phosphorylated AMP-activated protein kinase). These should be the focus of further investigations.</p> <h2 scrollto-destination=388939896 id="388939896" class="section-title js-splitscreen-section-title" data-legacy-id=ehac495-s4>Conclusion</h2> <p class="chapter-para">Proteomics is rapidly emerging as an innovative approach to gaining potential insights into the mechanisms of disease and drug action. Our proteomics analysis of blood samples taken from participants pooled from two trials of empagliflozin in heart failure identified differential expression of a small select group of circulating proteins following SGLT2 inhibition. The biological effects of differentially expressed proteins on the heart were primarily focused on the promotion of autophagic flux, but they also included favourable effects to reduce oxidative stress, inhibit inflammation and fibrosis, and enhance the energy stores and the repair and regenerative capacity of the heart. The effects of differentially expressed proteins in the kidney involved the enhancement of renal autophagy, suppression of renal inflammation and fibrosis, and promotion of renal tubular integrity and regeneration as well as compensatory mechanisms that can limit the ability of SGLT2 inhibitors to produce sustained increases in sodium and water excretion. The actions of differentially expressed proteins identified in patients with heart failure are consistent with the findings of experimental studies that have linked the benefits of SGLT2 inhibitors on the heart and kidney to their actions on autophagy, inflammation and fibrosis, and cellular stress and viability. Our findings suggest that the results of these experimental studies are likely to be highly relevant to the clinical setting.</p> <h2 scrollto-destination=388939898 id="388939898" class="backsection-title js-splitscreen-backsection-title" data-legacy-id=ehac495-s5>Supplementary material</h2> <p class="chapter-para"><span class="link link-data-supplement" data-supplement-target="sup1"></span><span class="content-section supplementary-material"><a path-from-xml="sup1" href="https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/eurheartj/43/48/10.1093_eurheartj_ehac495/3/ehac495_supplementary_data.docx?Expires=1735388495&Signature=zA00q1xAsZPX7AwS49UAXOgQJJ1gZ7haV~9~97-7DY1lGwxZMLfDyZoDwyw~kCMVTw-7DYJlcaPoZLPfdtZ2mNHSAHUcGGO9TEgXGihBB7gS-v8d~L-WR1zeSAj591~qbGGhtxXLyGb5NIJo6fMs5vNQo7zQlsrEIAWeCG9KD6dvw-EskodnMB~s9Xk7HzpJzgBA~onAUlYsJeEtLd97yRG~g9GoJpXILo4fSB1yOHtzEfL6OdCJj8Ui2c-jFL90PAP~mEws62f6Pt2Yjkv2ft8TXcaF2GfTgpuig56B8Bz~VlK8RCs08NcHwrbluqZeWrqxZ64ybBXVnZDnoRdTgw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA">Supplementary material</a></span> is available at <em>European Heart Journal</em> online.</p> <h2 scrollto-destination=388939900 id="388939900" class="backacknowledgements-title js-splitscreen-backacknowledgements-title" data-legacy-id=ack1>Acknowledgements</h2> <p class="chapter-para">Graphical assistance was provided by 7.4 Limited and supported financially by Boehringer Ingelheim.</p> <h2 scrollto-destination=388939902 id="388939902" class="backsection-title js-splitscreen-backsection-title" data-legacy-id=ehac495-s6>Funding</h2> <p class="chapter-para">The EMPEROR-Reduced and Preserved trials were funded by Boehringer Ingelheim and Eli Lilly (EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977 and EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).</p> <h2 scrollto-destination=388939904 id="388939904" class="dataavailabilitystatement-title js-splitscreen-dataavailabilitystatement-title" data-legacy-id=ehac495-s7>Data availability</h2> <p class="chapter-para">To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to clinical study data pertinent to the development of the publication. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data when it becomes available on Vivli—Center for Global Clinical Research Data, and earliest after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete, and other criteria are met. Please visit Medical & Clinical Trials | Clinical Research | MyStudyWindow for further information. <a class="link link-uri openInAnotherWindow" href="https://www.mystudywindow.com/msw/datasharing" target="_blank">https://www.mystudywindow.com/msw/datasharing</a>.</p> <h2 scrollto-destination=388939906 id="388939906" class="backreferences-title js-splitscreen-backreferences-title" data-legacy-id=ref1>References</h2> <div class="ref-list js-splitview-ref-list"><div content-id="ehac495-B1" class="js-splitview-ref-item" data-legacy-id="ehac495-B1"><div class="refLink-parent"><span class="refLink"><a name="jumplink-ehac495-B1" href="javascript:;" aria-label="jumplink-ehac495-B1" data-id=""></a></span></div><div class="ref false"><div id="ref-auto-ehac495-B1" class="ref-content " data-id="ehac495-B1"><span class="label title-label">1</span><div class="mixed-citation citation"><p class="mixed-citation-compatibility"><span class="person-group"><span class="name string-name"><div 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Prognostic importance of NT-proBNP and effect of empagliflozin in the EMPEROR-reduced trial</div>. <div class="source ">J Am Coll Cardiol</div> <div class="year">2021</div>;<div class="volume">78</div>:<div class="fpage">1321</div>–<div class="lpage">1332</div>.</p><div class="citation-links"></div><div class="citation-links"><p class="citation-links-compatibility"><span class="google-scholar-ref-link"><a class="openInAnotherWindow" href="https://scholar.google.com/scholar_lookup?title=Packer%20M%3B%20EMPEROR-reduced%20trial%20committees%20and%20investigators.%20Prognostic%20importance%20of%20NT-proBNP%20and%20effect%20of%20empagliflozin%20in%20the%20EMPEROR-reduced%20trial&author=JL%20Januzzi&author=F%20Zannad&author=SD%20Anker&author=J%20Butler&author=G%20Filippatos&author=SJ%20Pocock&publication_year=2021&journal=J%20Am%20Coll%20Cardiol&volume=78&pages=1321-1332" target="_blank">Google Scholar</a></span></p><div class="crossref-doi js-ref-link"><a class="openInAnotherWindow" href="http://dx.doi.org/10.1016/j.jacc.2021.07.046" target="_blank">Crossref</a></div><div class="adsDoiReference hide"><a class="openInAnotherWindow" href="http://adsabs.harvard.edu/cgi-bin/basic_connect?qsearch=10.1016%2Fj.jacc.2021.07.046" target="_blank">Search ADS</a></div><div class="xslopenurl empty-target"><span class="inst-open-url-holders" data-targetId="10.1016%2Fj.jacc.2021.07.046"> </span></div><div class="pub-id"><a href="http://www.ncbi.nlm.nih.gov/pubmed/34556318" class="link link-pub-id openInAnotherWindow" target="_blank">PubMed</a></div><p class="citation-links-compatibility"><span class="worldcat-reference-ref-link js-worldcat-preview-ref-link" style="display:none"><a class="openInAnotherWindow" href="https://www.worldcat.org/search?q=ti:Packer%20M%3B%20EMPEROR-reduced%20trial%20committees%20and%20investigators.%20Prognostic%20importance%20of%20NT-proBNP%20and%20effect%20of%20empagliflozin%20in%20the%20EMPEROR-reduced%20trial&qt=advanced&dblist=638" target="_blank">WorldCat</a></span></p> </div></div></div></div></div></div>  <div class="widget widget-ArticlePubStateInfo widget-instance-OUP_ArticlePubStateInfo"> </div> <div class="article-metadata-standalone-panel clearfix"></div> <h2 class="authorNotes-section-title" id="authorNotesSectionTitle" scrollto-destination="authorNotesSectionTitle">Author notes</h2> <div content-id="ehac495-FM1" class="footnote"><span class="fn"><div class="footnote-content"><p class="footnote-compatibility">Faiez Zannad and João Pedro Ferreira Co-first authors.</p></div></span></div><div content-id="ehac495-FM2" class="footnote"><span class="fn"><div class="footnote-content"><p class="footnote-compatibility"><strong>Conflict of interest:</strong> F.Z. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer and, Cellprothera, other from CVCT, and Cardiorenal, outside the submitted work. J.P.F. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work. J.B. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave and Vifor, outside the submitted work. G.F. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Medtronic, Vifor, Servier, Novartis, Bayer, Amgen and Boehringer Ingelheim, outside the submitted work. J.L.J., a Trustee of the American College of Cardiology, a Board member of Imbria Pharmaceuticals, has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics, consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics, and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia and Takeda. M.S. and M.Z. are employees of Boehringer Ingelheim. M.S. is an employee of Elderbrook Solutions. S.J.P. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work. S.A. reports personal fees from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Abbott Vascular, Vifor, personal fees from Bayer, Boehringer Ingelheim, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis and Servier, outside the submitted work. N.S. has consulted for Amgen, Astrazeneca, Boehringer Ingelheim, Eli-Lilly, Hanmi Pharmaceuticals, Novo Nordisk, Novartis, Novartis, Sanofi and Pfizer and received grant support from Boehringer Ingelheim. S.D.A. reports grants and personal fees from Vifor Int. and Abbott Vascular, and personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor Int. Personal fees from Boehringer Ingelheim during the conduct of the study. M.P. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Abbvie, Actavis, Altimmune, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, Salamandra, outside the submitted work.</p></div></span></div><div class="copyright copyright-statement">© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.</div><div class="license"><div class="license-p">This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (<a class="link link-uri openInAnotherWindow" href="https://creativecommons.org/licenses/by-nc/4.0/" target="_blank">https://creativecommons.org/licenses/by-nc/4.0/</a>), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. 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