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Kidney Int. 2015 Aug;88(2):286-98. doi: 10.1038/ki.2015.121. Epub 2015 May 6.

Smad3 deficiency protects mice from obesity-induced podocyte injury that precedes insulin resistance.

Author information

1
Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
2
1] Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia [2] Department of Physiology, Monash University, Clayton, VIC, Australia.
3
Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
4
Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
5
Florida State University College of Medicine, Tallahassee, Florida, USA.
6
Division of Nephrology, Department of Internal Medicine, West China Hospital of Sichuan University, Chengdu, People's Republic of China.
7
Department of Nephrology, Monash Health and Monash University Department of Medicine, Clayton, VIC, Australia.

Abstract

Signaling by TGF-β/Smad3 plays a key role in renal fibrosis. As obesity is one of the major risk factors of chronic and end-stage renal disease, we studied the role of Smad3 signaling in the pathogenesis of obesity-related renal disease. After switching to a high fat diet, the onset of Smad3 C-terminal phosphorylation, increase in albuminuria, and the early stages of peripheral and renal insulin resistance occurred at 1 day, and 4 and 8 weeks, respectively, in C57BL/6 mice. The loss of synaptopodin, a functional marker of podocytes, and phosphorylation of the Smad3 linker region (T179 and S213) appeared after 4 weeks of the high fat diet. This suggests a temporal pattern of Smad3 signaling activation leading to kidney injury and subsequent insulin resistance in the development of obesity-related renal disease. In vivo, Smad3 knockout attenuated the high fat diet-induced proteinuria, renal fibrosis, overall podocyte injury, and mitochondrial dysfunction in podocytes. In vitro palmitate caused a rapid activation of Smad3 in 30 min, loss of synaptopodin in 2 days, and impaired insulin signaling in 3 days in isolated mouse podocytes. Blockade of either Smad3 phosphorylation by SIS3 (a Smad3 inhibitor) or T179 phosphorylation by flavopiridol (a CDK9 inhibitor) prevented the palmitate-induced loss of synaptopodin and mitochondrial function in podocytes. Thus, Smad3 signaling plays essential roles in obesity-related renal disease and may be a novel therapeutic target.

PMID:
25945408
DOI:
10.1038/ki.2015.121
[Indexed for MEDLINE]

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