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Calcineurin (CaN) inhibitors are effective in reducing proteinuria. However, their molecular mechanism is still not fully understood. Angiopoietin\u2010like\u20104 (ANGPTL4) is a secreted protein that mediates proteinuria in podocyte\u2010related nephropathy. In this study, we established a puromycin aminonucleoside (PAN)\u2010induced minimal\u2010change disease (MCD) rat model and a cultured podocyte injury model. We found that CaN inhibitors protected against PAN\u2010induced podocyte injury, accompanied by an inhibition of Nfatc1 and Angptl4 both in vivo<\/jats:italic> and in vitro<\/jats:italic>. Nfatc1<\/jats:italic> overexpression and knockdown experiments indicated that Angptl4 was regulated by Nfatc1<\/jats:italic> in podocytes. ChIP assays further demonstrated that Nfatc1 increased Angptl4<\/jats:italic> expression by binding to the Angptl4<\/jats:italic> promoter. In addition, overexpression and knockdown of Angptl4<\/jats:italic> revealed that Angptl4<\/jats:italic> directly induced rearrangement of the cytoskeleton of podocytes, reduced the expression of synaptopodin, and enhanced PAN\u2010induced podocyte apoptosis. Furthermore, in a cohort of 83 MCD and 94 membranous nephropathy (MN) patients, we found increased expression of serum ANGPTL4 compared to 120 healthy controls, and there were close correlations between serum ANGPTL4 and Alb, urinary protein, urinary Alb, eGFR, Scr, and BUN in MCD patients. No obvious correlation was found in MN patients. Immunofluorescence studies indicated that increased ANGPTL4 in MCD and MN patients was located mostly in podocytes. In conclusion, our results demonstrate that CaN inhibitors ameliorate PAN\u2010induced podocyte injury by targeting Angptl4 through the NFAT pathway, and Angptl4 plays a vital role in podocyte injury and is involved in human podocyte\u2010related nephropathy. \u00a9 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5512","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T02:04:00Z","timestamp":1595210640000},"page":"227-238","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Calcineurin inhibitors ameliorate PAN<\/scp>\u2010induced podocyte injury through the NFAT\u2013Angptl4<\/scp> pathway"],"prefix":"10.1002","volume":"252","author":[{"given":"Xiujin","family":"Shen","sequence":"first","affiliation":[{"name":"Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State Administration of Traditional Chinese Medicine Hangzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the National State Administration of Traditional Chinese Medicine Hangzhou PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province; National Key Clinical Department of Kidney Diseases; Institute of Nephrology, Zhejiang University; The Third Grade Laboratory under the 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