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

Yu Bo Yang Sun, Xinli Qu, Victor Howard, Lie Dai, Xiaoyun Jiang, Yi Ren, Ping Fu, Victor G Puelles, David J Nikolic-Paterson, Georgina Caruana, John F Bertram, Mark W Sleeman, Jinhua Li

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25 Citations (Scopus)

Abstract

Signaling by TGF-beta/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.Kidney International advance online publication, 6 May 2015; doi:10.1038/ki.2015.121.
Original languageEnglish
Pages (from-to)286 - 298
Number of pages13
JournalKidney International
Volume88
Issue number2
DOIs
Publication statusPublished - Aug 2015

Keywords

  • SMAD3
  • renal disease
  • Obesity
  • Diabetes

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