A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models
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Author(s)
Zhou, Yiming
Castonguay, Philip
Clark, Abbe R.
Dvela-Levitt, Moran
Kim, Sookyung
Sieber, Jonas
Wieder, Nicolas
Jung, Ji Yong
Andreeva, Svetlana
Reichardt, Jana
Date Issued
December 2017
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Zhou, Yiming et al. “A Small-Molecule Inhibitor of TRPC5 Ion Channels Suppresses Progressive Kidney Disease in Animal Models.” Science 358, 6368 (December 2017): 1332–1336 © 2017 The Authors
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Author's final manuscript
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.
MIT Department
Institute for Medical Engineering and Science
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/SCIENCE.AAL4178
