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 2

LPS- and PS-induced in situ podocyte Ca2+ transients are reduced in isolated glomeruli from Trpc5-KO mice.

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LPS- and PS-induced in situ podocyte Ca2+ transients are reduced in isol...
(A) Approach for imaging Ca2+ in podocytes in situ on intact, acutely isolated mouse glomeruli. Podocytes — located on the exterior surface of the isolated glomerulus, as shown — were efficiently loaded with Fura-2 and displayed measurable changes in Ca2+ in response to various stimuli. (B) LPS mediated Ca2+ influx (arrows) in glomeruli of WT mice, but the response was attenuated in Trpc5-KO glomeruli. (C) Quantification of peak transient amplitude (at Δt = 1 min) revealed a significantly greater response in WT (n = 24) versus Trpc5-KO (n = 10) glomeruli, attributed to TRPC5-mediated Ca2+ influx. (D) PS mediated Ca2+ influx (arrows) in WT glomeruli, but the response was attenuated in Trpc5-KO glomeruli. (E) Quantification of peak transient amplitude revealed a significantly greater response in WT versus Trpc5-KO glomeruli (n = 19 per group), attributed to TRPC5-mediated Ca2+ influx. Original magnification, ×400 (A, B, and D). Boxed regions are shown enlarged in B and D (enlarged ×9 and ×3, respectively). **P < 0.01, ***P < 0.001, Student’s t test.