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Science DOI:10.1126/science.aal4178

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

Publication TypeJournal Article
Year of Publication2017
AuthorsZhou, Y, Castonguay, P, Sidhom, E-H, Clark, AR, Dvela-Levitt, M, Kim, S, Sieber, J, Wieder, N, Jung, JYong, Andreeva, S, Reichardt, J, Dubois, F, Hoffmann, SC, Basgen, JM, Montesinos, MS, Weins, A, Johnson, AC, Lander, ES, Garrett, MR, Hopkins, CR, Greka, A
JournalScience
Volume358
Issue6368
Pages1332-1336
Date Published2017 12 08
ISSN1095-9203
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.

DOI10.1126/science.aal4178
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29217578?dopt=Abstract

Alternate JournalScience
PubMed ID29217578
Grant ListR01 DK095045 / DK / NIDDK NIH HHS / United States
R01 DK099465 / DK / NIDDK NIH HHS / United States
R01 DK103658 / DK / NIDDK NIH HHS / United States
K08 DK083511 / DK / NIDDK NIH HHS / United States
R56 DK093746 / DK / NIDDK NIH HHS / United States
U54 MD007598 / MD / NIMHD NIH HHS / United States
R01 DK103658 / DK / NIDDK NIH HHS / United States
F31 CA195701 / CA / NCI NIH HHS / United States
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