| Literature DB >> 29217578 |
Yiming Zhou1,2, Philip Castonguay1,2, Eriene-Heidi Sidhom1,2, Abbe R Clark1,2, Moran Dvela-Levitt1,2, Sookyung Kim1,2, Jonas Sieber1,2, Nicolas Wieder1,2, Ji Yong Jung1,3, Svetlana Andreeva1, Jana Reichardt1, Frank Dubois1, Sigrid C Hoffmann4, John M Basgen5, Mónica S Montesinos1,2, Astrid Weins1,6, Ashley C Johnson7, Eric S Lander2, Michael R Garrett7, Corey R Hopkins8, Anna Greka1,2.
Abstract
Progressive kidney diseases are often associated with scarring of the kidney's filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.Entities:
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Year: 2017 PMID： 29217578 PMCID： PMC6014699 DOI： 10.1126/science.aal4178
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728