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Podocyte, the gatekeeper of the glomerular filtration barrier, is a primary target for growth factor and Ca 2+  signaling whose perturbation leads to proteinuria. However, the effects of insulin action on store-operated Ca 2+  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 Ca 2+ -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.

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