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

• DOI: 10.1073/pnas.0903458106
• Publication Date: 2009-08-14T02:14:08Z
• Authors: Ivica Grgic; Eva Kiss; Brajesh P. Kaistha; Christoph Busch; Michael Kloss; Julia Sautter; Anja Müller; Anuradha Kaistha; Claudia Schmidt; Girija Raman; Heike Wulff; Frank Strutz; Hermann-Josef Gröne; Ralf Köhler; Joachim Hoyer
• Keywords: Mice, Knockout; 0301 basic medicine; Patch-Clamp Techniques; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Cell Cycle; Gene Expression; Apoptosis; Fibroblasts; Flow Cytometry; Intermediate-Conductance Calcium-Activated Potassium Channels; Kidney; Fibrosis; Cell Line; Membrane Potentials; Mice; 03 medical and health sciences; Animals; Pyrazoles; Fibroblast Growth Factor 2; RNA, Messenger; Cell Proliferation

Proliferation of interstitial fibroblasts is a hallmark progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca 2+ -activated K + channel (K 3.1) has been proposed to promote mitogenesis several cell types and contribute disease states characterized by excessive proliferation. Here, we hypothesized that 3.1 activity pivotal for fibroblast proliferation deficiency or pharmacological blockade suppresses development fibrosis. We found mitogenic stimulation up-regulated murine via MEK-dependent mechanism selective functions potently inhibited G 0 /G 1 arrest. Renal induced unilateral ureteral obstruction (UUO) mice was paralleled robust up-regulation affected kidneys. Mice lacking −/− ) showed significant reduction fibrotic marker expression, tubulointerstitial damage, collagen deposition αSMA cells kidneys after UUO, whereas functional parenchyma better preserved. Pharmacological treatment with the blocker TRAM-34 similarly attenuated progression UUO-induced wild-type rats. In conclusion, our data demonstrate involved fibrogenesis suggest may represent therapeutic target disease.