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.
View: Text | PDF
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

×

Figure 7

TRPC5 inhibition protects against PS- or LPS-induced filter barrier disruption.

Options: View larger image (or click on image) Download as PowerPoint
TRPC5 inhibition protects against PS- or LPS-induced filter barrier disr...
(A) PS induced FPE. Coperfusion of 10 μM ML204 in PS-perfused mice preserved FPs, similar to HBSS controls. (B) ML204 treatment conferred protection from FPE (HBSS, 1.84 ± 0.08 FPs/μm GBM; PS, 1.16 ± 0.08 FPs/μm GBM; PS+ML204, 1.78 ± 0.2 FPs/μm GBM) (n = 6–7 animals and 90–150 images per group). (C) LPS injection led to FPE. Treatment of LPS-injected mice with 20 mg/kg/d ML204 i.p. mitigated FPE. (D) FP numbers in ML204-treated animals (PBS, 2.21 ± 0.07 FPs/μm GBM; LPS, 1.67 ± 0.10 FPs/μm GBM; LPS+ML204, 2.04 ± 0.04 FPs/μm GBM) (n = 3–4 animals and 60 images per group). (E) PBS or PBS+ML204 injection did not induce albuminuria in WT mice. After LPS injection, WT mice developed significant albuminuria, which was significantly reduced after ML204 treatment (n = 5–12 animals/group). Original magnification, ×15,000 (A and C). *P < 0.05, ***P < 0.001, ****P < 0.0001, ANOVA.