Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels

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

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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.
Original languageEnglish
JournalProceedings of the National Academy of Science of the United States of America
Volume106
Issue number34
Pages (from-to)14518-14523
ISSN0027-8424
DOIs
Publication statusPublished - 2009

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    Grgic, I., Kiss, E., Kaistha, B. P., Busch, C., Kloss, M., Sautter, J., Müller, A., Kaistha, A., Schmidt, C., Raman, G., Wulff, H., Strutz, F., Gröne, H-J., Köhler, R., & Hoyer, J. (2009). Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels. Proceedings of the National Academy of Science of the United States of America, 106(34), 14518-14523. https://doi.org/10.1073/pnas.0903458106