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.
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Authors | Minoru Satoh, Hajime Nagasu, Yoshitaka Morita, Terry P Yamaguchi, Yashpal S Kanwar, Naoki Kashihara |
Journal | American journal of physiology. Renal physiology
(Am J Physiol Renal Physiol)
Vol. 303
Issue 12
Pg. F1641-51
(Dec 15 2012)
ISSN: 1522-1466 [Electronic] United States |
PMID | 23034937
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Glucuronidase
- Klotho Proteins
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Topics |
- Animals
- Cell Cycle
(physiology)
- Cells, Cultured
- Disease Models, Animal
- Female
- Fibrosis
- Glucuronidase
(genetics, physiology)
- In Vitro Techniques
- Kidney
(pathology, physiopathology)
- Kidney Diseases
(pathology, physiopathology, prevention & control)
- Klotho Proteins
- Male
- Mice
- Mice, Mutant Strains
- Mice, Transgenic
- Plasmids
- Transfection
- Ureteral Obstruction
(complications, pathology, physiopathology)
- Wnt Signaling Pathway
(physiology)
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