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.
Highlights
Podocyte, the gatekeeper of the glomerular filtration barrier, is a primary target for growth factor and Ca2+ signaling whose perturbation leads to proteinuria
In non-excitable epithelial cells, the major Ca2+ influx is mediated by TRPC and store-operated Ca2+ (SOC) channels that are activated by phospholipase C (PLC)-linked Gαq-coupled receptors or RTKs5,24
We examined whether store-operated Ca2+ entry (SOCE) is another functional Ca2+ entry mechanism in isolated glomeruli and podocytes in addition to TRPC5 and TRPC6
Summary
The gatekeeper of the glomerular filtration barrier, is a primary target for growth factor and Ca2+ signaling whose perturbation leads to proteinuria. Acute infusion of insulin elicits transient albuminuria under euglycemic conditions in humans[18] These studies demonstrate that insulin receptor signaling has an ambivalent action on podocytes’ function in maintaining the kidney filter integrity. While Orai[1] activation by acute insulin exposure causes reversible actin remodeling and slit-diaphragm plasticity, chronic insulin stimulation of Orai[1] leads to irreversible abnormalities causing filter barrier disruption and pathologic proteinuria. This demonstrates a requirement of a fine-tuned insulin signaling; an aberrant insulin signaling may threaten podocyte [Ca2+]i homeostasis and glomerular functions
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