Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling

Am J Physiol Renal Physiol. 2012 Dec 15;303(12):F1641-51. doi: 10.1152/ajprenal.00460.2012. Epub 2012 Oct 3.

Abstract

Augmented Wnt signaling has been implicated in many fibrotic diseases including obstructive nephropathy. Soluble form Klotho has been reported to function as a secreted Wnt antagonist. In this study, we tested whether Klotho protein could reduce renal fibrosis by inhibition of Wnt signaling. Transgenic mice that overexpressed Klotho, wild-type mice, and Klotho hetero mutant mice underwent unilateral ureteral obstruction (UUO). In some Klotho hetero mutant mice, Klotho-encoding plasmid was transferred into the skeletal muscle by electroporation. UUO induced activation of Wnt signaling in wild-type but less in Klotho transgenic mice. Enhanced tubulointerstitial fibrosis in wild-type mice was also attenuated in Klotho transgenic mice. In contrast, Wnt signaling and concomitant tubulointerstitial fibrosis were further augmented in Klotho hetero mutant mice after UUO compared with wild-type mice. In Klotho-encoding plasmid-transfected Klotho hetero mutant mice, however, Wnt signaling was markedly reduced accompanied by a decrease in extracellular matrix deposition after UUO. In vitro studies showed that stimulation of Wnt3a induced prolonged cell cycle arrest at G(2)/M phase, with a resultant increase in production of fibrogenic cytokines. Cotreatment with Klotho bypassed the G(2)/M arrest and reduced fibrogenic cytokine production. In conclusion, Klotho is a critical negative regulator of Wnt signaling and a suppressor of renal fibrosis in the obstructed kidney model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / physiology
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Fibrosis
  • Glucuronidase / genetics
  • Glucuronidase / physiology*
  • In Vitro Techniques
  • Kidney / pathology*
  • Kidney / physiopathology
  • Kidney Diseases / pathology
  • Kidney Diseases / physiopathology
  • Kidney Diseases / prevention & control*
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Plasmids
  • Transfection
  • Ureteral Obstruction / complications*
  • Ureteral Obstruction / pathology
  • Ureteral Obstruction / physiopathology
  • Wnt Signaling Pathway / physiology*

Substances

  • Glucuronidase
  • klotho protein