Inhibition of the TRPC5 ion channel protects the kidney filter
Thomas Schaldecker, … , Astrid Weins, Anna Greka
Thomas Schaldecker, … , Astrid Weins, Anna Greka
Published November 15, 2013
Citation Information: J Clin Invest. 2013;123(12):5298-5309. https://doi.org/10.1172/JCI71165.
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Research Article Nephrology

Inhibition of the TRPC5 ion channel protects the kidney filter

Abstract

An intact kidney filter is vital to retention of essential proteins in the blood and removal of waste from the body. Damage to the filtration barrier results in albumin loss in the urine, a hallmark of cardiovascular disease and kidney failure. Here we found that the ion channel TRPC5 mediates filtration barrier injury. Using Trpc5-KO mice, a small-molecule inhibitor of TRPC5, Ca2+ imaging in isolated kidney glomeruli, and live imagining of podocyte actin dynamics, we determined that loss of TRPC5 or its inhibition abrogates podocyte cytoskeletal remodeling. Inhibition or loss of TRPC5 prevented activation of the small GTP-binding protein Rac1 and stabilized synaptopodin. Importantly, genetic deletion or pharmacologic inhibition of TRPC5 protected mice from albuminuria. These data reveal that the Ca2+-permeable channel TRPC5 is an important determinant of albuminuria and identify TRPC5 inhibition as a therapeutic strategy for the prevention or treatment of proteinuric kidney disease.

Authors

Thomas Schaldecker, Sookyung Kim, Constantine Tarabanis, Dequan Tian, Samy Hakroush, Philip Castonguay, Wooin Ahn, Hanna Wallentin, Hans Heid, Corey R. Hopkins, Craig W. Lindsley, Antonio Riccio, Lisa Buvall, Astrid Weins, Anna Greka

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Figure 6

Inhibition of muscarinic receptor–mediated TRPC5 activity prevents podocyte damage.

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Inhibition of muscarinic receptor–mediated TRPC5 activity prevents podoc...
(A) The muscarinic receptor agonist Cch induces a significant increase in Ca2+ transients in podocytes located on acutely isolated glomeruli from WT mice but not from Trpc5-KO mice. (B) Quantification of averaged peak amplitude at Δt = 1 min (n = 11 glomeruli per group). (C) Peak amplitude of Cch-induced Ca2+ transients in podocytes on acutely isolated glomeruli was attenuated by 3 μM ML204. (D) Quantification of averaged peak amplitude at Δt = 1 min (n = 12 glomeruli [Cch], 10 glomeruli [Cch+ML204]). (E) Loss of stress fibers induced by 100 μM Cch was blocked by ML204. (F) Significant rescue of stress fiber formation by ML204 (n = 90 images/condition). Scale bar: 50 μm (C). Original magnification, ×400 (E). **P < 0.01, ***P < 0.001, Student’s t test (B and D); ****P < 0.00001, ANOVA (F).