Document Detail


Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling.
MedLine Citation:
PMID:  23034937     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Minoru Satoh; Hajime Nagasu; Yoshitaka Morita; Terry P Yamaguchi; Yashpal S Kanwar; Naoki Kashihara
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  303     ISSN:  1522-1466     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-17     Completed Date:  2013-04-02     Revised Date:  2013-12-18    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F1641-51     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Cycle / physiology
Cells, Cultured
Disease Models, Animal
Female
Fibrosis
Glucuronidase / genetics,  physiology*
Kidney / pathology*,  physiopathology
Kidney Diseases / pathology,  physiopathology,  prevention & control*
Male
Mice
Mice, Mutant Strains
Mice, Transgenic
Plasmids
Transfection
Ureteral Obstruction / complications*,  pathology,  physiopathology
Wnt Signaling Pathway / physiology*
Grant Support
ID/Acronym/Agency:
DK-60635/DK/NIDDK NIH HHS; R01 DK060635/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
EC 3.2.1.31/Glucuronidase; EC 3.2.1.31/klotho protein
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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