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

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca2+-activated K+ channel (K Ca3.1) has been proposed to promote mitogenesis in several cell types and contribute to disease states characterized by excessive proliferation. Here, we hypothesized that KCa3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of KCa3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated KCa3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of KCa3.1 functions potently inhibited fibroblast proliferation by G0/G 1 arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of KCa3.1 in affected kidneys. Mice lacking KCa3.1 (KCa3.1 -/-) 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 Ca3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild-type mice and rats. In conclusion, our data demonstrate that KCa3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that KCa3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease.

Original languageEnglish (US)
Pages (from-to)14518-14523
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number34
DOIs
StatePublished - Aug 25 2009

Keywords

  • Fibroblasts
  • Ion channels
  • Kidney
  • Organ fibrosis

ASJC Scopus subject areas

  • General

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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 Sciences of the United States of America, 106(34), 14518-14523. https://doi.org/10.1073/pnas.0903458106