title: Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling.
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.
authors.affiliation: Dept. of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama Japan. msatoh@med.kawasaki-m.ac.jp
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Hajime
authors.initials: H
authors.lastname: Nagasu
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Morita
authors.forename: Terry P
authors.initials: TP
authors.lastname: Yamaguchi
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
authors.forename: Naoki
authors.initials: N
authors.lastname: Kashihara
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005966:Glucuronidase / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D007674:Kidney Diseases / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010957:Plasmids; D014162:Transfection; D014517:Ureteral Obstruction / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D005966:Glucuronidase; D000090265:Klotho Proteins