{"title":"Cdc42 Activation in Anti-nephrin Antibody-Induced Nephropathy.","authors":"Ying Zhang, Yoshiyasu Fukusumi, Hidenori Yasuda, Guoqing Chang, Mutsumi Kayaba, Hiroshi Kawachi","doi":"10.1681/ASN.0000000728","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>A subset of minimal change nephrotic syndrome was reported to be induced by autoantibodies against nephrin. We have reported that rats injected with murine anti-nephrin antibody showed proteinuria. However, its precise pathogenic mechanisms remain unclear.</p><p><strong>Methods: </strong>The initiation events of podocyte disturbance caused by anti-nephrin antibodies were analyzed using an in vivo rat model and in vitro assays with rat isolated glomeruli and human cultured podocytes. To elucidate the role of ephrin-B1 at the slit diaphragm, podocyte-specific ephrin-B1 knockout mice were analyzed.</p><p><strong>Results: </strong>Nephrin-binding ephrin-B1 at slit diaphragm interacted with Par6 and interfered with the binding of Par6 with cdc42. Anti-nephrin antibodies caused the phosphorylations of nephrin and ephrin-B1 in a TRPC6-mediated Ca2+ influx-dependent manner. Phosphorylated ephrin-B1 was dissociated from nephrin and also from Par6. Par6, released by ephrin-B1, interacted with cdc42. The binding of Par6 stabilized cdc42 and consequently promoted cdc42 activity. Elevated cdc42 activity increased calcineurin activity and consequently activated Snail. The activated Snail negatively regulated the mRNA expressions of the slit diaphragm functional molecules, nephrin and ephrin-B1. Elevated cdc42 activity activated Stat3 independently of calcineurin. The activated Stat3 brought on the expression of claudin1, a tight junction molecule. The altered expressions of these molecules at the protein level were observed in the rat anti-nephrin antibody-induced nephropathy when the rats showed proteinuria.</p><p><strong>Conclusions: </strong>Ephrin-B1 at slit diaphragm suppresses cdc42 activity by preventing the interaction of Par6 with cdc42 and functions to keep the specialized phenotype of podocytes. Elevated cdc42 activity induced by the binding of Par6, released by the phosphorylated ephrin-B1, is a critical initiation event leading to proteinuria in the anti-nephrin antibody-induced nephropathy.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3000,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of The American Society of Nephrology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1681/ASN.0000000728","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: A subset of minimal change nephrotic syndrome was reported to be induced by autoantibodies against nephrin. We have reported that rats injected with murine anti-nephrin antibody showed proteinuria. However, its precise pathogenic mechanisms remain unclear.
Methods: The initiation events of podocyte disturbance caused by anti-nephrin antibodies were analyzed using an in vivo rat model and in vitro assays with rat isolated glomeruli and human cultured podocytes. To elucidate the role of ephrin-B1 at the slit diaphragm, podocyte-specific ephrin-B1 knockout mice were analyzed.
Results: Nephrin-binding ephrin-B1 at slit diaphragm interacted with Par6 and interfered with the binding of Par6 with cdc42. Anti-nephrin antibodies caused the phosphorylations of nephrin and ephrin-B1 in a TRPC6-mediated Ca2+ influx-dependent manner. Phosphorylated ephrin-B1 was dissociated from nephrin and also from Par6. Par6, released by ephrin-B1, interacted with cdc42. The binding of Par6 stabilized cdc42 and consequently promoted cdc42 activity. Elevated cdc42 activity increased calcineurin activity and consequently activated Snail. The activated Snail negatively regulated the mRNA expressions of the slit diaphragm functional molecules, nephrin and ephrin-B1. Elevated cdc42 activity activated Stat3 independently of calcineurin. The activated Stat3 brought on the expression of claudin1, a tight junction molecule. The altered expressions of these molecules at the protein level were observed in the rat anti-nephrin antibody-induced nephropathy when the rats showed proteinuria.
Conclusions: Ephrin-B1 at slit diaphragm suppresses cdc42 activity by preventing the interaction of Par6 with cdc42 and functions to keep the specialized phenotype of podocytes. Elevated cdc42 activity induced by the binding of Par6, released by the phosphorylated ephrin-B1, is a critical initiation event leading to proteinuria in the anti-nephrin antibody-induced nephropathy.
期刊介绍：
The Journal of the American Society of Nephrology (JASN) stands as the preeminent kidney journal globally, offering an exceptional synthesis of cutting-edge basic research, clinical epidemiology, meta-analysis, and relevant editorial content. Representing a comprehensive resource, JASN encompasses clinical research, editorials distilling key findings, perspectives, and timely reviews.
Editorials are skillfully crafted to elucidate the essential insights of the parent article, while JASN actively encourages the submission of Letters to the Editor discussing recently published articles. The reviews featured in JASN are consistently erudite and comprehensive, providing thorough coverage of respective fields. Since its inception in July 1990, JASN has been a monthly publication.
JASN publishes original research reports and editorial content across a spectrum of basic and clinical science relevant to the broad discipline of nephrology. Topics covered include renal cell biology, developmental biology of the kidney, genetics of kidney disease, cell and transport physiology, hemodynamics and vascular regulation, mechanisms of blood pressure regulation, renal immunology, kidney pathology, pathophysiology of kidney diseases, nephrolithiasis, clinical nephrology (including dialysis and transplantation), and hypertension. Furthermore, articles addressing healthcare policy and care delivery issues relevant to nephrology are warmly welcomed.
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