A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models | Zendy

Yiming Zhou | Zendy; Philip Castonguay | Zendy; Eriene-Heidi Sidhom | Zendy; Abbe R. Clark | Zendy; Moran DvelaLevitt | Zendy; Sookyung Kim | Zendy; Jonas Sieber | Zendy; Nicolas Wieder | Zendy; Ji Yong Jung | Zendy; С. Г. Андреева | Zendy; Jana Reichardt | Zendy; Frank Dubois | Zendy; Sigrid Hoffmann | Zendy; John M. Basgen | Zendy; Mónica S. Montesinos | Zendy; Astrid Weins | Zendy; Ashley C. Johnson | Zendy; Eric S. Lander | Zendy; Michael R. Garrett | Zendy; Corey R. Hopkins | Zendy; Anna Greka | Zendy

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A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Author(s) -

Yiming Zhou,

Philip Castonguay,

Eriene-Heidi Sidhom,

Abbe R. Clark,

Moran DvelaLevitt,

Sookyung Kim,

Jonas Sieber,

Nicolas Wieder,

Ji Yong Jung,

С. Г. Андреева,

Jana Reichardt,

Frank Dubois,

Sigrid Hoffmann,

John M. Basgen,

Mónica S. Montesinos,

Astrid Weins,

Ashley C. Johnson,

Eric S. Lander,

Michael R. Garrett,

Corey R. Hopkins,

Anna Greka

Publication year - 2017

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aal4178

Subject(s) - trpc5 , podocyte , focal segmental glomerulosclerosis , kidney disease , glomerulosclerosis , proteinuria , renal function , kidney , rac1 , endocrinology , medicine , biology , microbiology and biotechnology , ion channel , receptor , signal transduction , trpc1

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.

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