Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 303, Issue 12, Pages F1641-F1651Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00460.2012
Keywords
cell cycle; G(2)/M; unilateral ureteral obstruction; fibrogenic cytokine
Categories
Funding
- Japan Society for the Promotion of Science [21591046]
- Research Project Grant from Kawasaki Medical School [21-208, 22-A73]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK-60635]
- Grants-in-Aid for Scientific Research [21591046] Funding Source: KAKEN
Ask authors/readers for more resources
Satoh M, Nagasu H, Morita Y, Yamaguchi TP, Kanwar YS, Kashihara N. Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling. Am J Physiol Renal Physiol 303: F1641-F1651, 2012. First published October 3, 2012; doi:10.1152/ajprenal.00460.2012.-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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available