A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models
Science  08 Dec 2017:
Vol. 358, Issue 6368, pp. 1332-1336
DOI: 10.1126/science.aal4178
 
Progressive kidney diseases, whether caused by obesity, hypertension, diabetes, or rare genetic mutations, often have the same outcome: The cells responsible for filtering the blood are destroyed. Reporting today in Science, a team led by researchers from the Broad Institute of MIT and Harvard, Brigham and Women's Hospital, and Harvard Medical School describes a new approach to prevent death in these essential kidney cells. Studying multiple animal models of kidney disease, the team discovered a compound that can impede loss of the filtration cells and restore kidney function. The work, inspired by an investigation into a genetic form of the condition, has the potential to affect therapeutic research for millions of people suffering from progressive kidney diseases.
 
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.
 
The researchers 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.
 
 
Edited by: M.Hezarkhani  M.D. UROLOGIST
TEHRAN  UNIVERSITY