Insulin-activated store-operated Ca2+ entry via Orai1 induces podocyte actin remodeling and causes proteinuria

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 and Seung-Kuy Cha ()
Additional contact information
Ji-Hee Kim: Yonsei University Wonju College of Medicine
Kyu-Hee Hwang: Yonsei University Wonju College of Medicine
Bao T. N. Dang: Yonsei University Wonju College of Medicine
Minseob Eom: Yonsei University Wonju College of Medicine
In Deok Kong: Yonsei University Wonju College of Medicine
Yousang Gwack: University of California
Seyoung Yu: Yonsei University College of Medicine
Heon Yung Gee: Yonsei University College of Medicine
Lutz Birnbaumer: National Institute of Environmental Health Sciences
Kyu-Sang Park: Yonsei University Wonju College of Medicine
Seung-Kuy Cha: Yonsei University Wonju College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-26900-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26900-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-26900-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().