부산대학교 도서관

Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance [Ca.sup.2+]-activated [K.sup.+] 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.sup.-/-]) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and [alpha][SMA.sup.+] 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. ion channels | fibroblasts | kidney | organ fibrosis