title: 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.affiliation: Department of Internal Medicine and Nephrology, Philipps-University, 35033 Marburg, Germany.
authors.forename: Ivica
authors.initials: I
authors.lastname: Grgic
authors.forename: Eva
authors.initials: E
authors.lastname: Kiss
authors.forename: Brajesh P
authors.initials: BP
authors.lastname: Kaistha
authors.forename: Christoph
authors.initials: C
authors.lastname: Busch
authors.forename: Michael
authors.initials: M
authors.lastname: Kloss
authors.forename: Julia
authors.initials: J
authors.lastname: Sautter
authors.forename: Anja
authors.initials: A
authors.lastname: Müller
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kaistha
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmidt
authors.forename: Girija
authors.initials: G
authors.lastname: Raman
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Frank
authors.initials: F
authors.lastname: Strutz
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
authors.forename: Joachim
authors.initials: J
authors.lastname: Hoyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D011720:Pyrazoles; D012333:RNA, Messenger; C411671:TRAM 34; D016222:Fibroblast Growth Factor 2
references.citation: J Am Soc Nephrol. 2008 Dec;19(12):2282-7
references.pmid: 18987304
references.citation: Science. 1982 Oct 29;218(4571):474-5
references.pmid: 7123245
references.citation: Circ Res. 2000 Sep 15;87(6):496-503
references.pmid: 10988242
references.citation: Lab Invest. 1993 May;68(5):557-65
references.pmid: 8497127
references.citation: Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):704-9
references.pmid: 15662023
references.citation: Kidney Int. 2000 Nov;58(5):2028-43
references.pmid: 11044223
references.citation: Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8151-6
references.pmid: 10884437
references.citation: Exp Nephrol. 1995 Sep-Oct;3(5):308-18
references.pmid: 7583053
references.citation: Curr Opin Nephrol Hypertens. 2004 May;13(3):279-84
references.pmid: 15073485
references.citation: J Am Soc Nephrol. 2005 Jul;16(7):2044-51
references.pmid: 15888566
references.citation: J Clin Pathol. 1997 Feb;50(2):123-7
references.pmid: 9155692
references.citation: Clin J Am Soc Nephrol. 2007 Sep;2(5):906-13
references.pmid: 17702727
references.citation: Oncogene. 2007 Aug 2;26(35):5107-14
references.pmid: 17310992
references.citation: Vascul Pharmacol. 2002 Jan;38(1):35-41
references.pmid: 12378821
references.citation: Kidney Int. 1992 Jan;41(1):14-23
references.pmid: 1593850
references.citation: Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1084-9
references.pmid: 18309114
references.citation: Histochem Cell Biol. 2008 Jul;130(1):141-55
references.pmid: 18449560
references.citation: J Membr Biol. 1999 Dec 1;172(3):249-57
references.pmid: 10568794
references.citation: J Biol Chem. 2000 May 5;275(18):13677-82
references.pmid: 10788486
references.citation: Kidney Int. 2000 Apr;57(4):1521-38
references.pmid: 10760088
references.citation: J Membr Biol. 1996 Nov;154(2):91-107
references.pmid: 8929284
references.citation: Curr Opin Nephrol Hypertens. 2001 May;10(3):315-20
references.pmid: 11342792
references.citation: Nat Rev Cancer. 2007 Jul;7(7):519-30
references.pmid: 17585332
references.citation: Nephrol Dial Transplant. 1997 Jan;12(1):43-50
references.pmid: 9027772
references.citation: Transplantation. 2003 Aug 15;76(3):480-9
references.pmid: 12923432
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8687-92
references.pmid: 15173588
references.citation: Blood. 2008 Apr 15;111(8):3991-7
references.pmid: 18192510
references.citation: Am J Pathol. 2005 Jul;167(1):285-98
references.pmid: 15972972
references.citation: Kidney Int. 2001 Feb;59(2):579-92
references.pmid: 11168939
references.citation: Circulation. 2003 Sep 2;108(9):1119-25
references.pmid: 12939222
references.citation: J Biol Chem. 2004 Nov 12;279(46):47681-7
references.pmid: 15347667
references.citation: J Am Soc Nephrol. 2006 Nov;17(11):2992-8
references.pmid: 17035610
references.citation: Nat Med. 2003 Jul;9(7):964-8
references.pmid: 12808448
references.citation: Am J Physiol Cell Physiol. 2004 Jul;287(1):C125-34
references.pmid: 14985237
references.citation: Stem Cells. 2007 Mar;25(3):697-706
references.pmid: 17170067
references.citation: Mol Cell. 2005 Oct 7;20(1):45-52
references.pmid: 16209944
references.citation: J Biol Chem. 1999 May 21;274(21):14838-49
references.pmid: 10329683
references.citation: J Clin Invest. 2007 Mar;117(3):524-9
references.pmid: 17332879
references.citation: Nat Clin Pract Nephrol. 2006 Feb;2(2):101-8
references.pmid: 16932401
references.citation: Cell Physiol Biochem. 2006;18(1-3):47-56
references.pmid: 16914889
references.citation: J Clin Invest. 2002 Aug;110(3):341-50
references.pmid: 12163453
references.citation: J Clin Invest. 2008 Sep;118(9):3025-37
references.pmid: 18688283
references.citation: Nephron. 1999;82(1):39-50
references.pmid: 10224483
references.citation: Physiol Rev. 2001 Oct;81(4):1415-59
references.pmid: 11581493
references.citation: J Biol Chem. 1997 Dec 26;272(52):32723-6
references.pmid: 9407042
references.citation: Br J Pharmacol. 2006 Aug;148(7):909-17
references.pmid: 16770324
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4219-23
references.pmid: 8633044
references.citation: Circ Res. 2006 Sep 1;99(5):537-44
references.pmid: 16873714
references.citation: J Biol Chem. 2000 Nov 24;275(47):37137-49
references.pmid: 10961988
references.citation: Am J Pathol. 2005 Nov;167(5):1193-205
references.pmid: 16251405
references.citation: Exp Nephrol. 1995 Mar-Apr;3(2):134-9
references.pmid: 7773633
references.citation: Mol Pharmacol. 2004 Mar;65(3):630-8
references.pmid: 14978241