Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 34, Pages 14518-14523Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0903458106
Keywords
ion channels; fibroblasts; kidney; organ fibrosis
Categories
Funding
- German Kidney Foundation
- German Society of Hypertension
- Deutsche Forschungsgemeinschaft [SFB 593/project A11, SFB 405/project B10]
- University Medical Center Giessen and Marburg
- National Institutes of Health [GM076063]
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Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca2+-activated K+ channel (K(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(Ca)3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of K(Ca)3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated K(Ca)3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of K(Ca)3.1 functions potently inhibited fibroblast proliferation by G(0)/G(1) arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of K(Ca)3.1 in affected kidneys. Mice lacking K(Ca)3.1 (K(Ca)3.1(-/-)) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and alpha SMA(+) cells in kidneys after UUO, whereas functional renal parenchyma was better preserved. Pharmacological treatment with the selective K(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(Ca)3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that K(Ca)3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease.
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