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

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.

Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans

“…A few recent papers show increased cell proliferation in TIF models and indicate that limiting cell proliferation could improve fibrosis development (45)(46)(47). Therefore, it might be interesting to speculate the role of cell proliferation in humans with TIF and in murine TIF models.…”

Intermediate-Conductance Ca2+-Activated K+ Channel, KCa3.1, as a Novel Therapeutic Target for Benign Prostatic Hyperplasia

“…3). Recent studies have shown that K Ca such as K Ca 3.1 and small-conductance Ca 2ϩ -activated K ϩ channel (SK Ca 2/ K Ca 2.2) participate in the modulation of cell proliferation in several types of cells and that their pharmacological blockade and down-regulation inhibit cell proliferation by G 0 /G 1 arrest (Morimoto et al, 2007;Wang et al, 2007;Grgic et al, 2009). This suggests that the inhibitory effects of TRAM-34 on in vivo cell proliferation in the implanted UGS of stromal BPH model rats may be responsible for the termination of cell cycle progression from G 0 /G 1 by TRAM-34 treatment.…”

IHG-1 Promotes Mitochondrial Biogenesis by Stabilizing PGC-1α

“…40 All of these factors have been implicated in the pathogenesis or treatment of various conditions resulting in renal fibrosis. [41][42][43][44] Significantly, IHG-1 expression has been shown to be increased in both DN and an experimental model of renal fibrosis (UUO) in which TIF is well modeled. 4,45 Oxidative stress is a key early event in both of these conditions.…”