Renal fibrosis is attenuated by targeted disruption of KCa3.1 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 alphaSMA(+) 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.

• 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 34 Pg. 14518-23 (Aug 25 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19706538 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Intermediate-Conductance Calcium-Activated Potassium Channels
• Kcnn4 protein, mouse
• Pyrazoles
• RNA, Messenger
• TRAM 34
• Fibroblast Growth Factor 2

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Fibroblast Growth Factor 2 (pharmacology)
• Fibroblasts (cytology, drug effects, physiology)
• Fibrosis (etiology, prevention & control)
• Flow Cytometry
• Gene Expression (drug effects)
• Intermediate-Conductance Calcium-Activated Potassium Channels (antagonists & inhibitors, genetics, physiology)
• Kidney (drug effects, metabolism, pathology)
• Membrane Potentials (drug effects)
• Mice
• Mice, Knockout
• Patch-Clamp Techniques
• Pyrazoles (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Ureteral Obstruction (complications)