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, Seung Kuy Cha

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4 Citations (Scopus)


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.

Original languageEnglish
Article number6537
JournalNature communications
Issue number1
Publication statusPublished - 2021 Dec

Bibliographical note

Funding Information:
We thank professors Shmuel Muallem (NIH), Joseph Yuan (University of North Texas), Joo Young Kim (Yonsei University), Chan Young Park (UNIST), and Peter Mundel (Harvard Medical School) for materials. We are grateful to professors Claes B Wollheim, Nicolas Demaurex (University of Geneva), Andreas Wiederkehr (Nestle Institute of Health Science), and Chou-Long Huang (University of Iowa) for critical reading and their comments on the manuscript. This study was supported by the Medical Research Center Program (2017R1A5A2015369) and the Basic Science Research Program (NRF-2010-0024789, 2013R1A1A2060764, 2015R1D1A1A01060454, 2017R1D1A3B03031760, and 2019R1A2C1084880) through the National Research Foundation of Korea, and the Intramural Research Program of the NIH (Z01-ES-101684 to L.B.).

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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