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Insulin-activated store-operated Ca 2+ entry via Orai1 induces podocyte actin remodeling and causes proteinuria

Authors
 Ji-Hee Kim  ;  Kyu-Hee Hwang  ;  Bao T N Dang  ;  Minseob Eom  ;  In Deok Kong  ;  Yousang Gwack  ;  Seyoung Yu  ;  Heon Yung Gee  ;  Lutz Birnbaumer  ;  Kyu-Sang Park  ;  Seung-Kuy Cha 
Citation
 NATURE COMMUNICATIONS, Vol.12(1) : 6537, 2021-11 
Journal Title
NATURE COMMUNICATIONS
Issue Date
2021-11
Abstract
Podocyte, the gatekeeper of the glomerular filtration barrier, is a primary target for growth factor and Ca2+ signaling whose perturbation leads to proteinuria. However, the effects of insulin action on store-operated Ca2+ entry (SOCE) in podocytes remain unknown. Here, we demonstrated that insulin stimulates SOCE by VAMP2-dependent Orai1 trafficking to the plasma membrane. Insulin-activated SOCE triggers actin remodeling and transepithelial albumin leakage via the Ca2+-calcineurin pathway in podocytes. Transgenic Orai1 overexpression in mice causes podocyte fusion and impaired glomerular filtration barrier. Conversely, podocyte-specific Orai1 deletion prevents insulin-stimulated SOCE, synaptopodin depletion, and proteinuria. Podocyte injury and albuminuria coincide with Orai1 upregulation at the hyperinsulinemic stage in diabetic (db/db) mice, which can be ameliorated by the suppression of Orai1-calcineurin signaling. Our results suggest that tightly balanced insulin action targeting podocyte Orai1 is critical for maintaining filter integrity, which provides novel perspectives on therapeutic strategies for proteinuric diseases, including diabetic nephropathy.
Files in This Item:
T202105338.pdf Download
DOI
10.1038/s41467-021-26900-w
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187242
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