title: Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling.
abstract: Aging is an independent risk factor for CKD, but the molecular mechanisms that link aging and CKD are not well understood. The antiaging protein Klotho may be an endogenous antagonist of Wnt/β-catenin signaling, which promotes fibrogenesis, suggesting that loss of Klotho may contribute to CKD through increased Wnt/β-catenin activity. Here, normal adult kidneys highly expressed Klotho in the tubular epithelium, but various models of nephropathy exhibited markedly less expression of Klotho. Loss of Klotho was closely associated with increased β-catenin in the diseased kidneys, suggesting an inverse correlation between Klotho and canonical Wnt signaling. In vitro, both full-length and secreted Klotho bound to multiple Wnts, including Wnt1, Wnt4, and Wnt7a. Klotho repressed gene transcription induced by Wnt but not by active β-catenin. Furthermore, Klotho blocked Wnt-triggered activation and nuclear translocation of β-catenin, as well as the expression of its target genes in tubular epithelial cells. Investigating potential mediators of Klotho loss in CKD, we found that TGF-β1 suppressed Klotho expression and concomitantly activated β-catenin; conversely, overexpression of Klotho abolished fibrogenic effects of TGF-β1. In two mouse models of CKD induced by unilateral ureteral obstruction or adriamycin, in vivo expression of secreted Klotho inhibited the activation of renal β-catenin and expression of its target genes. Secreted Klotho also suppressed myofibroblast activation, reduced matrix expression, and ameliorated renal fibrosis. Taken together, these results suggest that Klotho is an antagonist of endogenous Wnt/β-catenin activity; therefore, loss of Klotho may contribute to kidney injury by releasing the repression of pathogenic Wnt/β-catenin signaling.
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University and Guangdong Provincial Institute of Nephrology, Guangzhou, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Li
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Tan
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005355:Fibrosis; D005966:Glucuronidase / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051436:Renal Insufficiency, Chronic / Q000209:etiology*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C495270:CTNNB1 protein, human; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D005966:Glucuronidase; D000090265:Klotho Proteins
references.citation: JAMA. 2007 Nov 7;298(17):2038-47
references.pmid: 17986697
references.citation: J Am Soc Nephrol. 2009 Apr;20(4):765-76
references.pmid: 19297557
references.citation: Expert Opin Ther Targets. 2011 Sep;15(9):1073-83
references.pmid: 21623684
references.citation: Biochem Biophys Res Commun. 2001 Feb 2;280(4):1015-20
references.pmid: 11162628
references.citation: Development. 2009 Jan;136(1):161-71
references.pmid: 19060336
references.citation: Curr Opin Cell Biol. 2008 Apr;20(2):119-25
references.pmid: 18339531
references.citation: Am J Physiol Renal Physiol. 2009 Feb;296(2):F213-29
references.pmid: 18784259
references.citation: Semin Nephrol. 2007 May;27(3):309-20
references.pmid: 17533008
references.citation: Curr Opin Nephrol Hypertens. 2011 May;20(3):312-7
references.pmid: 21358327
references.citation: Curr Opin Nephrol Hypertens. 2012 May;21(3):323-8
references.pmid: 22388555
references.citation: Adv Exp Med Biol. 2012;728:25-40
references.pmid: 22396160
references.citation: Adv Exp Med Biol. 2012;728:126-57
references.pmid: 22396167
references.citation: J Am Soc Nephrol. 2011 Sep;22(9):1642-53
references.pmid: 21816937
references.citation: Gastroenterology. 2010 Apr;138(4):1384-94, 1394.e1-2
references.pmid: 20004202
references.citation: J Biol Chem. 2011 Mar 11;286(10):8655-8665
references.pmid: 21209102
references.citation: Am J Physiol Renal Physiol. 2007 Aug;293(2):F494-500
references.pmid: 17494089
references.citation: Kidney Int. 2011 Dec;80(11):1159-1169
references.pmid: 21832980
references.citation: J Am Soc Nephrol. 2005 Aug;16(8):2373-84
references.pmid: 15944336
references.citation: Nat Rev Nephrol. 2011 Aug 09;7(12):706-17
references.pmid: 21826079
references.citation: Kidney Int. 2012 Sep;82(5):537-47
references.pmid: 22622501
references.citation: J Am Soc Nephrol. 2009 Sep;20(9):1997-2008
references.pmid: 19628668
references.citation: J Am Soc Nephrol. 2004 Oct;15(10):2637-47
references.pmid: 15466268
references.citation: Am J Pathol. 2007 Sep;171(3):861-71
references.pmid: 17675578
references.citation: Kidney Int. 2008 Oct;74(8):1004-8
references.pmid: 18633347
references.citation: Curr Biol. 2001 Jun 26;11(12):951-61
references.pmid: 11448771
references.citation: Biochim Biophys Acta. 2009 Oct;1790(10):1049-58
references.pmid: 19230844
references.citation: J Biol Chem. 2010 Aug 6;285(32):24665-75
references.pmid: 20519507
references.citation: Science. 2007 Aug 10;317(5839):803-6
references.pmid: 17690294
references.citation: Cell. 2012 Jun 8;149(6):1192-205
references.pmid: 22682243
references.citation: J Am Soc Nephrol. 2011 Jul;22(7):1315-25
references.pmid: 21719790
references.citation: Nat Rev Nephrol. 2012 Jun 05;8(7):423-9
references.pmid: 22664739
references.citation: Diabetologia. 2012 Jan;55(1):255-66
references.pmid: 22016045
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):856-61
references.pmid: 11792841
references.citation: Kidney Int. 2010 Jun;77(11):962-73
references.pmid: 20375988
references.citation: EMBO J. 2006 Nov 29;25(23):5603-13
references.pmid: 17093497
references.citation: Nat Med. 2010 May;16(5):535-43, 1p following 143
references.pmid: 20436483
references.citation: J Am Soc Nephrol. 2011 Jan;22(1):124-36
references.pmid: 21115613
references.citation: J Am Soc Nephrol. 2012 Feb;23(2):294-304
references.pmid: 22095947
references.citation: Cardiovasc Res. 2004 Nov 1;64(2):331-6
references.pmid: 15485693
references.citation: Am J Transplant. 2009 Oct;9(10):2223-39
references.pmid: 19681821
references.citation: J Am Soc Nephrol. 2011 Jan;22(1):90-103
references.pmid: 21030600
references.citation: Front Biosci (Landmark Ed). 2009 Jan 01;14:2448-65
references.pmid: 19273211
references.citation: Kidney Int. 2008 Sep;74(6):710-20
references.pmid: 18614996
references.citation: Kidney Int. 2009 Jun;75(11):1145-1152
references.pmid: 19340094
references.citation: Am J Physiol Renal Physiol. 2012 May 15;302(10):F1252-64
references.pmid: 22338084
references.citation: Ageing Res Rev. 2009 Jan;8(1):43-51
references.pmid: 19022406