TRPC channels in proteinuric kidney disease

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The canonical transient receptor potential channel 6 (TRPC6) has been recently added to the growing number of genes involved in familial forms of proteinuric kidney disease, characterized by nephrosis and ultimate renal failure. Interestingly, all TRPC6 mutations known to date are gain of function mutations, suggesting that increased Ca+2 influx through TRPC6 channels leads to podocyte injury. The mechanisms for TRPC channel regulation in podocytes are largely unknown. Furthermore, the question remains whether an increase in Ca+2 influx through TRPC channels occurs in both genetic and acquired forms of proteinuric kidney disease. Our preliminary data suggest that TRPC1 and TRPC5 are expressed in glomerular podocytes, where, like TRPC6, they localize to podocyte foot processes, in the vicinity of slit diaphragms. Our adhesion assays and wound assays in podocytes demonstrate a striking translocation of channel to membrane ruffles, indicating that channel localization is a regulated process. Angiotensin induces prominent calcium transients in podocytes expressing the AT1R, and a significant portion of this calcium influx appears to be mediated by TRPC channels. Patch clamp experiments in podocytes confirm the presence of a TRPC-like current. Single channel recordings suggest that channel activity is regulated by channel translocation to the membrane. When membrane trafficking is disrupted by pharmacologic and molecular techniques in podocytes, the TRPC-like current is largely diminished, supporting the notion that channel activity is regulated by channel translocation to the membrane. Based on our preliminary work, we hypothesize that TRPC1 and TRPC5 form novel channels in podocytes, which, in concert with TRPC6, mediate Ca+2 influx by their regulated translocation to the plasma membrane in response to upstream signaling through the Angiotensin Type 1 Receptor. PUBLIC HEALTH RELEVANCE: This work on the role of TRPC channels in proteinuric kidney disease will help identify targets for the development of medications and therapies to treat and prevent diseases such as nephrotic syndrome and diabetic nephropathy, which currently affect many kidney disease patients worldwide.