TRPC-mediated calcium signaling in podocytes

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PROJECT SUMMARY Proteinuria is a major health-care problem, not only as a cardinal sign and prognostic marker of kidney disease, but also importantly, as an independent risk factor for cardiovascular morbidity and mortality. Kidney podocytes are important for the maintenance of the kidney filtration barrier. Early podocyte injury is characterized by dysregulation of Ca2+ signaling, leading to proteinuria, the inappropriate leakage of protein into the urine. Work by the PI and others has shown that Ca2+ signals, mediated by TRP (Transient Receptor Potential) channels, are enriched near the leading edge of migrating cells. Ongoing work in the PI's laboratory has shown that Ca2+ influx through TRPC5 and TRPC6 channels in podocytes is criticaly important for the cytoskeletal integrity of these cells. TRPC5-mediated Ca2+ influx induces Rac1 activation, thereby promoting podocyte migration. In contrast, TRPC6-mediated Ca2+ influx increases RhoA activity, inhibiting podocyte migration. Here we propose to test our central hypothesis that disruption of the critical balance between TRPC5 and TRPC6 signaling contributes to the pathogenesis of proteinuria. We are specificaly interested in the role of TRPC5 and Rac1 signaling in early phases of proteinuric kidney disease. To test this hypothesis, our first aim is to explore whether TRPC channels regulate actin dynamics by modulating synaptopodin and RhoGTPase activity in podocytes. In our second aim, we wil explore the in vivo role of podocyte TRPC5 signaling in the pathogenesis of proteinuria, and thus its potential as a new therapeutic target for diseases such as nephrotic syndrome, FSGS, diabetic and hypertensive nephropathy. This area of research is currently highly relevant to human disease, since TRPC-mediated podocyte damage leads to proteinuria, and in turn, proteinuria is a herald of chronic kidney disease and kidney failure, both of which are on the rise, and have been recently described by many observers as an impending epidemic. ! !