Renal fibrosis is attenuated by targeted disruption of K sub(Ca)3.1 potassium channels

Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca super(2+)-activated K super(+) channel (K sub(Ca)3.1) has been proposed to promote mitogenesis in several cell types and contribute to d...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 34; pp. 14518 - 14523
Main Authors:	Grgic, Ivica, Kiss, Eva, Kaistha, Brajesh P, Busch, Christoph, Kloss, Michael, Sautter, Julia, M1/4ller, Anja, Kaistha, Anuradha, Schmidt, Claudia, Raman, Girija, Wulff, Heike, Strutz, Frank, Grne, Hermann-Josef, Khler, Ralf, Hoyer, Joachim
Format:	Journal Article
Language:	English
Published:	01-01-2009
Online Access:	Get full text
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Summary:	Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca super(2+)-activated K super(+) channel (K sub(Ca)3.1) has been proposed to promote mitogenesis in several cell types and contribute to disease states characterized by excessive proliferation. Here, we hypothesized that K sub(Ca)3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of K sub(Ca)3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated K sub(Ca)3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of K sub(Ca)3.1 functions potently inhibited fibroblast proliferation by G sub(0)/G sub(1) arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of K sub(Ca)3.1 in affected kidneys. Mice lacking K sub(Ca)3.1 (K sub(Ca)3.1 super(-/-)) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and alpha SMA super(+) cells in kidneys after UUO, whereas functional renal parenchyma was better preserved. Pharmacological treatment with the selective K sub(Ca)3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild- type mice and rats. In conclusion, our data demonstrate that K sub(Ca)3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that K sub(Ca)3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-2
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0903458106