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

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Abstract
Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca 2+ -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 αSMA + 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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