Molecular mechanisms of AT1R signaling in FSGS

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DESCRIPTION (provided by applicant): Classical studies have revealed a central role for the Renin-Angiotensin system (RAS) in the emergence and progression of proteinuria and chronic kidney disease. Angiotensin Converting Enzyme Inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) are to date the treatment of choice for the delay of disease progression. Podocyte dysfunction, represented by proteinuria, foot process effacement (FPE) and disruption of the slit diaphragm (SD), is often the initial insult leading to progressive kidney disease. The identification of human mutations in the Ca2+-permeable ion channel TRPC6 as a cause of inherited Focal Segmental Glomerulosclerosis (FSGS) brought Ca2+ biology to the forefront of podocyte research. Our recently published work revealed that both TRPC5 and TRPC6 are important Ca2+ influx pathways in podocytes. The Renin-Angiotensin system (RAS) and RAS/Ca2+ signaling is critical for the structural and functional integrity of podocytes. Podocyte-specific transgenic overexpression of the Angiotensin II type 1 receptor (AT1R) in rats (AT1R Tg) results in podocyte hypertrophy, proteinuria, and ultimately FSGS, but the molecular mechanisms leading to disease are not well understood. Work in the PI's laboratory provided a mechanistic link between AT1R activation and subsequent Ca2+ influx in podocytes through TRPC5 and TRPC6 channels. TRPC5-mediated Ca2+ influx induces Rac1 activation, thereby promoting podocyte migration. TRPC5-mediated degradation of synaptopodin and loss of stress fibers can be rescued by CsA, placing TRPC5 upstream of calcineurin-mediated signaling in podocytes. Here we propose to test our hypothesis that AT1R-mediated activation of TRPC5 causes CsA-sensitive proteinuria and podocyte hypertrophy. At later stages, upregulation of TRPC6 abundance leads to excess Ca2+ toxicity and podocyte death. This area of research is highly relevant to human disease, because proteinuria and associated kidney disease is a major health-care problem affecting millions of people worldwide, and there are currently no targeted, podocyte-preserving therapies available in the clinic.