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

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.