Potassium channels: the 'master switch' of renal fibrosis?

Abstract

Progressive renal fibrosis resulting from proliferation of interstitial fibroblasts is a hallmark of chronic kidney failure, whatever the origin. The intermediate/small-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) promotes mitogenesis in several cell types by altering the membrane potential, thus enabling extracellular Ca(2+) entry. Grgic et al. evaluated the role of K(Ca)3.1 in renal fibroblast proliferation, testing whether deficiency or pharmacological blockade of K(Ca)3.1 suppressed development of renal fibrosis. Mitogens stimulated K(Ca)3.1 in murine renal fibroblasts via a MEK-dependent mechanism, while selective blockade of K(Ca)3.1 inhibited fibroblast proliferation by promoting G0/G1 arrest. In a classical model of renal fibrosis, mouse unilateral ureteral obstruction (UUO), robust up-regulation of K(Ca)3.1 was detectable in affected kidneys. K(Ca)3.1 KO mice showed reduced expression of fibrotic marker expression, less chronic tubulointerstitial damage, collagen deposition and alpha-smooth muscle+ cells after UUO, with better preservation of functional renal parenchyma. The selective K(Ca)3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild-type mice and rats. Thus, Grgic et al. believe that K(Ca)3.1 is involved in renal fibroblast proliferation and fibrogenesis, suggesting that K(Ca)3.1 may serve as a therapeutic target for the prevention of fibrotic kidney disease.