Proteinuria is a major health-care problem, not only as a cardinal sign and prognostic marker of kidneydisease, 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 ischaracterized by dysregulation of Ca2+ signaling, leading to proteinuria, the inappropriate leakage of proteininto 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 shownthat Ca2+ influx through TRPC5 and TRPC6 channels in podocytes is criticaly important for the cytoskeletalintegrity of these cells. TRPC5-mediated Ca2+ influx induces Rac1 activation, thereby promoting podocytemigration. 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 andTRPC6 signaling contributes to the pathogenesis of proteinuria. We are specificaly interested in the role ofTRPC5 and Rac1 signaling in early phases of proteinuric kidney disease. To test this hypothesis, our first aimis to explore whether TRPC channels regulate actin dynamics by modulating synaptopodin and RhoGTPaseactivity in podocytes. In our second aim, we wil explore the in vivo role of podocyte TRPC5 signaling in thepathogenesis of proteinuria, and thus its potential as a new therapeutic target for diseases such as nephroticsyndrome, FSGS, diabetic and hypertensive nephropathy.This area of research is currently highly relevant to human disease, since TRPC-mediated podocyte damageleads to proteinuria, and in turn, proteinuria is a herald of chronic kidney disease and kidney failure, both ofwhich are on the rise, and have been recently described by many observers as an impending epidemic.!!
Work in our laboratory has provided novel insights into TRPC-mediated Ca2+ signaling in podocytes, and specifically, in the role of TRPC5 in podocyte injury and early phases of proteinuric kidney disease. The goal of this application is to define the molecular mechanisms through which TRPC5 and TRPC6 channels regulate podocyte structure and function in health and disease, thereby paving the road for the development of novel anti-proteinuric treatment options.
