Adipose Serpina3c is induced by exercise to alleviate diabetic nephropathy in mice

  • J Adv Res. 2026 May 16:S2090-1232(26)00432-7. doi: 10.1016/j.jare.2026.05.037.
Ruo-Ying Li  1 ,  Jie-Ying Zhu  1 ,  Lin-Jing Yan  1 ,  Zi-Ang Zhao  1 ,  Shan Li  1 ,  Yang Li  1 ,  Wang-Jing Mu  1 ,  Meng-Ting Yin  1 ,  Hu-Min Chen  1 ,  Xin Li  1 ,  Ya-Lan Yang  1 ,  Quan Liu  1 ,  Le Li  1 ,  Liang Guo  2
Affiliations
  • 1. Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China.
  • 2. Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China. Electronic address: [email protected].
PMID: 42144061 DOI: 10.1016/j.jare.2026.05.037
Abstract

Exercise is an effective approach to slow down the progression of diabetic nephropathy (DN), but the underlying mediators remain incompletely understood. Here we demonstrate that exercise induces the expression of the adipokine Serpina3c in adipose tissue. Using adipocyte-specific knockout and overexpression mouse models combined with STZ-induced DN, we show that Serpina3c is important for exercise-induced renal protection. Adipose Serpina3c knockout exacerbated renal injury and abolished the benefits of exercise in alleviating DN, whereas adipose Serpina3c overexpression enhanced exercise-mediated protection. Mechanistically, Serpina3c binds to Wnt5a and competitively inhibits its interaction with the Cd146 receptor on renal tubular epithelial cells, thereby suppressing JNK phosphorylation and subsequent inflammation, Apoptosis, and fibrosis. Our findings establish adipose-derived Serpina3c as a key exerkine that mediates exercise-induced renal protection via inhibition of the renal Wnt5a/Cd146/JNK pathway.

Keywords
Apoptosis; Diabetic nephropathy; Exercise; Fibrosis; Inflammation; JNK phosphorylation; Renal tubular epithelial cells; Wnt5a/Cd146/JNK signaling pathway.
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