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<h3>Nephrology</h3> <div class='row'> <div class='small-10 medium-7 large-5 small-centered columns'> <ul class='tabs row' data-tab> <li class='tab-title small-6 centered active'> <a href='#articles'>269 Articles</a> </li> <li class='tab-title small-6 centered '> <a href='#posts'>11 Posts</a> </li> </ul> </div> </div> <div class='tabs-content'> <div class='content active' id='articles'> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/31?content=articles&page=2">2</a></li> <li><a href="/tags/31?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/31?content=articles&page=26">26</a></li> <li><a href="/tags/31?content=articles&page=27">27</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/31?content=articles&page=2">Next →</a></li></ul></div> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/190850">Unveiling mechanisms underlying kidney function changes during sex hormone therapy</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190850">Sarah A. van Eeghen, … , Daniël Raalte, Natalie J. Nokoff</a> <a class='hide-for-small show-more' data-reveal-id='article45959-more' href='#'> <div class='article-authors'> Sarah A. van Eeghen, … , Daniël Raalte, Natalie J. Nokoff </div> </a> <span class='article-published-at'> Published April 7, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI190850">https://doi.org/10.1172/JCI190850</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190850">Text</a> | <a href="/articles/view/190850/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190850' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45959-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190850">Unveiling mechanisms underlying kidney function changes during sex hormone therapy</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190850">Text</a></li> <li><a class="button tiny" href="/articles/view/190850/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Background: Men with chronic kidney disease (CKD) experience faster kidney function decline than women. Studies in individuals undergoing sex hormone therapy suggest a role for sex hormones, as estimated glomerular filtration rate (eGFR) increases with feminizing therapy and decreases with masculinizing therapy. However, effects on measured GFR (mGFR), glomerular and tubular function, and involved molecular mechanisms remain unexplored. Methods: This prospective, observational study included individuals initiating feminizing (estradiol and antiandrogens; n=23) or masculinizing (testosterone; n=21) therapy. Baseline and three-month assessments included mGFR (Iohexol clearance), kidney perfusion (para-aminohippuric acid clearance), tubular injury biomarkers, and plasma proteomics. Results: During feminizing therapy, mGFR and kidney perfusion increased (+3.6% and +9.1%, respectively; p<0.05), without increased glomerular pressure. Tubular injury biomarkers, including urine neutrophil gelatinase-associated lipocalin, EGF, monocyte chemoattractant protein-1, and chitinase 3-like protein 1 (YKL-40), decreased significantly (-53%, -42%, -45%, and -58%, respectively). During masculinizing therapy, mGFR and kidney perfusion remained unchanged, but urine YKL-40 and plasma TNFR-1 increased (+134% and +8%, respectively; p<0.05). Proteomic analysis revealed differential expression of 49 proteins during feminizing, and 356 proteins during masculinizing therapy. Many kidney-protective proteins were positively associated with estradiol and negatively associated with testosterone, including proteins involved in endothelial function (SFRP4, SOD3), inflammation reduction (TSG-6), and maintaining kidney tissue structure (agrin). Conclusion: Sex hormones influence kidney physiology, with estradiol showing protective effects on glomerular and tubular function, while testosterone predominantly exerts opposing effects. These findings emphasize the role of sex hormones in sexual dimorphism observed in kidney function and physiology and suggest new approaches for sex-specific precision medicine.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sarah A. van Eeghen, Laura Pyle, Phoom Narongkiatikhun, Ye Ji Choi, Wassim Obeid, Chirag R. Parikh, Taryn G. Vosters, Irene GM van Valkengoed, Merle M. Krebber, Daan J. Touw, Martin den Heijer, Petter Bjornstad, Daniël Raalte, Natalie J. Nokoff</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181164">Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/181164">Sindhuri Prakash, … , Jan Novak, Ali G. Gharavi</a> <a class='hide-for-small show-more' data-reveal-id='article45920-more' href='#'> <div class='article-authors'> Sindhuri Prakash, … , Jan Novak, Ali G. Gharavi </div> </a> <span class='article-published-at'> Published March 28, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI181164">https://doi.org/10.1172/JCI181164</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181164">Text</a> | <a href="/articles/view/181164/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181164' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45920-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181164">Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181164">Text</a></li> <li><a class="button tiny" href="/articles/view/181164/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Aberrant O-glycosylation of the IgA1 hinge region is a characteristic finding in patients with IgA nephropathy (IgAN) and is thought to contribute to immune-complex formation and kidney injury. Other studies have suggested that abnormalities in mucosal immunity and lymphocyte homing are major contributors to disease. We identified a family with IgAN segregating a heterozygous predicted loss-of-function (LOF) variant in GALNT14, the gene encoding N-acetylgalactosaminyltransferase 14, one of the enzymes involved in mucin-type protein O-glycosylation. While GALNT14 is expressed in IgA1-producing cells, carriers of the LOF variant did not have altered levels of poorly glycosylated IgA1, suggesting other disease mechanisms. Investigation of Galnt14 null mice revealed elevated serum IgA levels and ex vivo IgA production by B cells. These mice developed glomerular IgA deposition with aging and after induction of sterile colitis. Galnt14 null mice also displayed an attenuated mucin layer in the colon and redistribution of IgA-producing cells from mucosal to systemic sites. Adoptive-transfer experiments indicated impaired homing of spleen-derived Galnt14 deficient B lymphocytes, resulting in increased retention in peripheral blood. These findings suggest that abnormalities in O-glycosylation alter mucosal immunity and B lymphocyte homing, pointing to an expanded role of aberrant O-glycosylation in the pathogenesis of IgAN.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sindhuri Prakash, Nicholas J. Steers, Yifu Li, Elena Sanchez-Rodriguez, Miguel Verbitsky, Isabel Robbins, Jenna Simpson, Sharvari Pathak, Milan Raska, Colin Reily, Anna Ng, Judy Liang, Natalia DeMaria, Amanda Katiraei, Kelsey O'Stevens, Clara Fischman, Samantha Shapiro, Swetha Kodali, Jason McCutchan, Heekuk Park, Djamila Eliby, Marco Delsante, Landino Allegri, Enrico Fiaccadori, Monica Bodria, Maddalena Marasa, Elizabeth Raveche, Bruce A. Julian, Anne-Catrin Uhlemann, Krzysztof Kiryluk, Hong Zhang, Vivette D. D'Agati, Simone Sanna-Cherchi, Jan Novak, Ali G. Gharavi</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186633">Gene-environment interaction modifies the association between hyperinsulinemia and serum urate levels through SLC22A12</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186633">Wataru Fujii, … , Yuta Kochi, Shigeru Shibata</a> <a class='hide-for-small show-more' data-reveal-id='article45882-more' href='#'> <div class='article-authors'> Wataru Fujii, … , Yuta Kochi, Shigeru Shibata </div> </a> <span class='article-published-at'> Published March 18, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186633">https://doi.org/10.1172/JCI186633</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186633">Text</a> | <a href="/articles/view/186633/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186633' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45882-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186633">Gene-environment interaction modifies the association between hyperinsulinemia and serum urate levels through SLC22A12</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186633">Text</a></li> <li><a class="button tiny" href="/articles/view/186633/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND. Hyperinsulinemia and insulin resistance often accompany elevated serum urate levels (hyperuricemia), a highly heritable condition that triggers gout; however, the underlying mechanisms are unclear. METHODS. We evaluated the association between the index of hyperinsulinemia and the fractional excretion of urate (FEUA) in 162 outpatients. The underlying mechanisms were investigated through single-cell data analysis and kinase screening combined with cell culture experiments. In 377,358 participants of the UK Biobank (UKBB), we analyzed serum urate, hyperinsulinemia, and salt intake. We also examined gene-environment interactions using single nucleotide variants in SLC22A12, which encodes urate transporter 1 (URAT1). RESULTS. The index of hyperinsulinemia was inversely associated with FEUA independently of other covariates. Mechanistically, URAT1 cell-surface abundance and urate transport activity were regulated by URAT1-Thr408 phosphorylation, which was stimulated by hyperinsulinemia via AKT. Kinase screening and single-cell data analysis revealed that SGK1, induced by high salt, activated the same pathway, increasing URAT1. Arg405 was essential for these kinases to phosphorylate URAT1-Thr408. In UKBB participants, hyperinsulinemia and high salt intake were independently associated with increased serum urate levels. We found that SLC22A12 eQTL rs475688 synergistically enhanced the positive association between serum urate and hyperinsulinemia. CONCLUSION. URAT1 mediates the association between hyperinsulinemia and hyperuricemia. Our data provide evidence for the role of gene-environment interactions in determining serum urate levels, paving the way for personalized management of hyperuricemia. FUNDING. ACRO Research Grants of Teikyo University; JSPS; the Japanese Society of Gout and Uric & Nucleic Acids; Fuji Yakuhin; Nanken-Kyoten; Medical Research Center Initiative for High Depth Omics.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Wataru Fujii, Osamu Yamazaki, Daigoro Hirohama, Ken Kaseda, Emiko Kuribayashi-Okuma, Motonori Tsuji, Makoto Hosoyamada, Yuta Kochi, Shigeru Shibata</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186705">Acute kidney injury triggers hypoxemia by lung intravascular neutrophil retention that reduces capillary blood flow</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186705">Yohei Komaru, … , Daniel Kreisel, Andreas Herrlich</a> <a class='hide-for-small show-more' data-reveal-id='article45835-more' href='#'> <div class='article-authors'> Yohei Komaru, … , Daniel Kreisel, Andreas Herrlich </div> </a> <span class='article-published-at'> Published March 6, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186705">https://doi.org/10.1172/JCI186705</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186705">Text</a> | <a href="/articles/view/186705/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186705' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45835-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186705">Acute kidney injury triggers hypoxemia by lung intravascular neutrophil retention that reduces capillary blood flow</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186705">Text</a></li> <li><a class="button tiny" href="/articles/view/186705/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with unexplained hypoxemia that does not improve with dialysis. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induces rapid intravascular neutrophil retention in lung alveolar capillaries without extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of substantial lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote lung inflammation did not require cues from intravascular non-classical monocytes or tissue-resident alveolar macrophages. Instead, lung neutrophil retention depended on neutrophil chemoattractant CXCL2 released by activated classical monocytes. Comparative single-cell RNA-sequencing analysis of direct and remote lung inflammation revealed that alveolar macrophages are highly activated and produce CXCL2 only in direct lung inflammation. Establishing a CXCL2 gradient into the alveolus by intratracheal CXCL2 administration during AKI-induced remote lung inflammation enabled neutrophils to extravasate. We thus discovered important differences in lung neutrophil recruitment in direct versus remote lung inflammation and identified lung capillary neutrophil retention that negatively affects oxygenation by causing a ventilation-perfusion mismatch as a driver of AKI-induced hypoxemia.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yohei Komaru, Liang Ning, Carine Lama, Anusha Suresh, Eirini Kefaloyianni, Mark J. Miller, Shinichi Kawana, Hailey M. Shepherd, Wenjun Li, Daniel Kreisel, Andreas Herrlich</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/178813">Sequential carbonyl derivatives and hydrazone adduct formation on myeloperoxidase contribute to development of ANCA-vasculitis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/178813">Gang Xi, … , J. Charles Jennette, Ronald J. Falk</a> <a class='hide-for-small show-more' data-reveal-id='article45830-more' href='#'> <div class='article-authors'> Gang Xi, … , J. Charles Jennette, Ronald J. Falk </div> </a> <span class='article-published-at'> Published February 28, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI178813">https://doi.org/10.1172/JCI178813</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/178813">Text</a> | <a href="/articles/view/178813/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI178813' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45830-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/178813">Sequential carbonyl derivatives and hydrazone adduct formation on myeloperoxidase contribute to development of ANCA-vasculitis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/178813">Text</a></li> <li><a class="button tiny" href="/articles/view/178813/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Drug-induced autoimmune diseases are increasingly recognized although mechanistic insight into disease causation is lacking. Hydralazine exposure has been linked to autoimmune diseases, including anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Our hypothesis posits that hydralazine covalently binds to myeloperoxidase (MPO), triggering the autoimmune response in ANCA vasculitis. We in vitro observed formation of carbonyl derivatives on amine groups in the presence of acrolein. This facilitated the subsequent binding of hydralazine to heme-containing proteins, including MPO, via a Michael addition. Our studies demonstrated that carbonyl derivatives and hydrazone adducts induce conformational changes in the MPO heavy chain, potentially changing its immunogenicity. We identified hydrazone adducts on circulating MPO in patients with hydralazine-associated ANCA vasculitis. These patients exhibited elevated anti-MPO IgM levels, while anti-MPO IgG levels were comparable between hydralazine-associated and non-hydralazine-associated vasculitis patients. IgM isolated from hydralazine-associated MPO ANCA patients demonstrated a heightened affinity to hydralazine-modified MPO and activated neutrophil-like HL-60 cells. Hydralazine-modified MPO was pathogenic, as demonstrated by splenocyte transfer in a mouse model of ANCA vasculitis. Our findings unveil a mechanism of drug-induced autoimmunity wherein stepwise chemical modifications of MPO lead to conformational changes and hydrazone adduct formation producing a neoantigen to which pathogenic autoantibodies are generated.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Gang Xi, Elizabeth A. Mclnnis, Olivier Lardinois, Peiqi Hu, John S. Poulton, Meghan E. Free, Dhruti P. Chen, Evan M. Zeitler, Eveline Y. Wu, Nicole M. Orzechowski, Vimal K. Derebail, J. Charles Jennette, Ronald J. Falk</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180242">ZDHHC18 promotes renal fibrosis development by regulating HRAS palmitoylation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180242">Di Lu, … , Yuhang Jiang, Qi Wang</a> <a class='hide-for-small show-more' data-reveal-id='article45756-more' href='#'> <div class='article-authors'> Di Lu, … , Yuhang Jiang, Qi Wang </div> </a> <span class='article-published-at'> Published February 6, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI180242">https://doi.org/10.1172/JCI180242</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180242">Text</a> | <a href="/articles/view/180242/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180242' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45756-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180242">ZDHHC18 promotes renal fibrosis development by regulating HRAS palmitoylation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180242">Text</a></li> <li><a class="button tiny" href="/articles/view/180242/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Fibrosis is the final common pathway leading to end stage chronic kidney disease (CKD). However, the function of protein palmitoylation in renal fibrosis and underlying mechanisms remain unclear. In this study, we observed that the expression of the palmitoyltransferase ZDHHC18 was significantly elevated in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models, and was significantly upregulated in the fibrotic kidneys of chronic kidney disease patients. Functionally, tubule-specific deletion of ZDHHC18 attenuated tubular epithelial cells partial epithelial-to-mesenchymal transition (EMT), then reduced production of profibrotic cytokine and alleviates tubulointerstitial fibrosis. In contrast, ZDHHC18 overexpression exacerbated progressive renal fibrosis. Mechanistically, ZDHHC18 catalyzed the palmitoylation of HRAS, which is pivotal for its translocation to the plasma membrane and subsequent activation. HRAS palmitoylation promoted downstream phosphorylation of MEK/ERK and further activated RREB1, enhancing SMAD binding to the Snai1 cis-regulatory regions. Taken together, our findings suggest that ZDHHC18 plays a crucial role in renal fibrogenesis and presents a potential therapeutic target for combating kidney fibrosis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Di Lu, Gulibositan Aji, Guanyu Li, yue li, Wenlin Fang, Shuai Zhang, ruiqi yu, Sheng Jiang, xia gao, Yuhang Jiang, Qi Wang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185146">Targeting allograft inflammatory factor-1 reprograms kidney macrophages to enhance repair</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185146">Irma Husain, … , Edward B. Thorp, Xunrong Luo</a> <a class='hide-for-small show-more' data-reveal-id='article45705-more' href='#'> <div class='article-authors'> Irma Husain, … , Edward B. Thorp, Xunrong Luo </div> </a> <span class='article-published-at'> Published January 21, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI185146">https://doi.org/10.1172/JCI185146</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185146">Text</a> | <a href="/articles/view/185146/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185146' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45705-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185146">Targeting allograft inflammatory factor-1 reprograms kidney macrophages to enhance repair</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185146">Text</a></li> <li><a class="button tiny" href="/articles/view/185146/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The role of macrophages remains incompletely understood in kidney injury and repair. Their plasticity offers an opportunity to polarize them towards mediating injury resolution in both native and transplanted kidneys undergoing ischemia and/or rejection. Here, we show that infiltrating kidney macrophages augmented their AIF-1 expression after injury. Aif1 genetic deletion led to macrophage polarization towards a reparative phenotype while halting the development of kidney fibrosis. The enhanced repair was mediated by higher levels of anti-inflammatory and pro-regenerative markers leading to a reduction in cell death and increase in proliferation of kidney tubular epithelial cells following ischemic reperfusion injury. Adoptive transfer of Aif1-/- macrophages to Aif1+/+ mice conferred protection against ischemia reperfusion injury. Conversely, depletion of macrophages reversed the tissue-reparative effects in Aif1-/- mice. We further demonstrated an increased expression of AIF-1 in human kidney biopsies from native kidneys with acute kidney injury or chronic kidney disease, as well as in biopsies from kidney allografts undergoing acute or chronic rejection. We conclude that AIF-1 is a macrophage marker of renal inflammation, and its targeting uncouples macrophage reparative functions from profibrotic functions. Thus, therapies inhibiting AIF-1 when ischemic injury is inevitable have the potential to reduce the global burden of kidney disease.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Irma Husain, Holly Shah, Collin Z. Jordan, Naveen R. Natesh, Olivia K. Fay, Yanting Chen, Jamie R. Privratsky, Hiroki Kitai, Tomokazu Souma, Shyni Varghese, David N. Howell, Edward B. Thorp, Xunrong Luo</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186769">Passive transfer of patient-derived anti-nephrin autoantibodies causes a podocytopathy with minimal change lesions</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186769">Felicitas E. Hengel, … , Tobias B. Huber, Nicola M. Tomas</a> <a class='hide-for-small show-more' data-reveal-id='article45700-more' href='#'> <div class='article-authors'> Felicitas E. Hengel, … , Tobias B. Huber, Nicola M. Tomas </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186769">https://doi.org/10.1172/JCI186769</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186769">Text</a> | <a href="/articles/view/186769/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186769' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45700-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186769">Passive transfer of patient-derived anti-nephrin autoantibodies causes a podocytopathy with minimal change lesions</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186769">Text</a></li> <li><a class="button tiny" href="/articles/view/186769/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p> </p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Felicitas E. Hengel, Silke Dehde, Oliver Kretz, Jonas Engesser, Tom Zimmermann, Tobias B. Huber, Nicola M. Tomas</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179882">Intestinal <i>Cyp24a1</i> regulates vitamin D locally independent of systemic regulation by renal <i>Cyp24a1</i> in mice</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/179882">Michaela A.A. Fuchs, … , Tomokazu Souma, Myles Wolf</a> <a class='hide-for-small show-more' data-reveal-id='article45626-more' href='#'> <div class='article-authors'> Michaela A.A. Fuchs, … , Tomokazu Souma, Myles Wolf </div> </a> <span class='article-published-at'> Published December 17, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024. <a href="https://doi.org/10.1172/JCI179882">https://doi.org/10.1172/JCI179882</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179882">Text</a> | <a href="/articles/view/179882/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179882' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45626-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179882">Intestinal <i>Cyp24a1</i> regulates vitamin D locally independent of systemic regulation by renal <i>Cyp24a1</i> in mice</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179882">Text</a></li> <li><a class="button tiny" href="/articles/view/179882/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Vitamin D regulates mineral homeostasis. The most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is synthesized by CYP27B1 from 25-dihydroxyvitamin D (25D) and inactivated by CYP24A1. Human monogenic diseases and genome-wide association studies support a critical role for CYP24A1 in regulation of mineral homeostasis, but little is known about its tissue-specific effects. Here, we describe the responses of mice with inducible global deletion, kidney-specific, and intestine-specific deletion of Cyp24a1 to dietary calcium challenge and chronic kidney disease (CKD). Global and kidney-specific Cyp24a1 deletion caused similar syndromes of systemic vitamin D intoxication: elevated circulating 1,25D, 25D and fibroblast growth factor 23 (FGF23), activation of vitamin D target genes in the kidney and intestine, hypercalcemia, and suppressed parathyroid hormone (PTH). In contrast, mice with intestine-specific Cyp24a1 deletion demonstrated activation of vitamin D target genes exclusively in the intestine despite no changes in systemic vitamin D levels. In response to a high calcium diet, PTH was suppressed despite normal serum calcium. In mice with CKD, intestinal Cyp24a1 deletion decreased PTH and FGF23 without precipitating hypercalcemia. These results implicate kidney CYP24A1 in systemic vitamin D regulation while independent local effects of intestinal CYP24A1 could be targeted to treat secondary hyperparathyroidism in CKD.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Michaela A.A. Fuchs, Alexander Grabner, Melody Shi, Susan L. Murray, Emily J. Burke, Nejla Latic, Venkataramana Thiriveedi, Jatin Roper, Shintaro Ide, Koki Abe, Hiroki Kitai, Tomokazu Souma, Myles Wolf</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180347">Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180347">Silvana Bazua-Valenti, … , Juan Lorenzo B. Pablo, Anna Greka</a> <a class='hide-for-small show-more' data-reveal-id='article45607-more' href='#'> <div class='article-authors'> Silvana Bazua-Valenti, … , Juan Lorenzo B. Pablo, Anna Greka </div> </a> <span class='article-published-at'> Published December 16, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/24">134(24)</a>:e180347. <a href="https://doi.org/10.1172/JCI180347">https://doi.org/10.1172/JCI180347</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180347">Text</a> | <a href="/articles/view/180347/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180347' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/180347/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/180000/180347/small/JCI180347.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45607-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180347">Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180347">Text</a></li> <li><a class="button tiny" href="/articles/view/180347/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain–containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD-UMOD, and in mutant-UMOD-knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Silvana Bazua-Valenti, Matthew R. Brown, Jason Zavras, Magdalena Riedl Khursigara, Elizabeth Grinkevich, Eriene-Heidi Sidhom, Keith H. Keller, Matthew Racette, Moran Dvela-Levitt, Catarina Quintanova, Hasan Demirci, Sebastian Sewerin, Alissa C. Goss, John Lin, Hyery Yoo, Alvaro S. Vaca Jacome, Malvina Papanastasiou, Namrata Udeshi, Steven A. Carr, Nina Himmerkus, Markus Bleich, Kerim Mutig, Sebastian Bachmann, Jan Halbritter, Stanislav Kmoch, Martina Živná, Kendrah Kidd, Anthony J. Bleyer, Astrid Weins, Seth L. Alper, Jillian L. Shaw, Maria Kost-Alimova, Juan Lorenzo B. Pablo, Anna Greka</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/31?content=articles&page=2">2</a></li> <li><a href="/tags/31?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/31?content=articles&page=26">26</a></li> <li><a href="/tags/31?content=articles&page=27">27</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/31?content=articles&page=2">Next →</a></li></ul></div> </div> </div> </div> <div class='content ' id='posts'> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/31?content=posts&page=2">2</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/31?content=posts&page=2">Next →</a></li></ul></div> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/489">Local TNF mediates free cholesterol–dependent podocyte injury</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/489"><div class='article-metadata'> In this episode, Alessia Fornoni reveals that TNF promotes free cholesterol–dependent podocyte apoptosis via an NFATc1/ ABCA1-dependent mechanism. <br> <span class='published-at smaller'> Published August 2, 2016 </span> </div> </a></div> <div class='small-12 columns'> <a href="/tags/107"><span style='margin-right: 6px' class="label-article-type">Video Abstracts</span></a><a href="/tags/31"><span style='margin-right: 6px' class="label-specialty">Nephrology</span></a> </div> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <h5><a href="/posts/478">Anti-THSD7A is a bona fide culprit in membranous nephropathy</a></h5> </div> </div> <div class='row'> <div class='large-8 columns'> <div class='row'> <div class='small-12 columns'> <a href="/posts/478"><div class='article-metadata'> Nicola M. 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