Myokine SIRPα exacerbates kidney disease in diabetes

Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein alpha (SIRP alpha), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRP alpha on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRP alpha-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRP alpha monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRP alpha increased. Genetic deletion of muscle SIRP alpha protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced intramuscular fat deposition when compared with flox mice on HFD. Moreover, mSIRP alpha-KO mice displayed enhanced kidney tubular fatty acid oxidation (FAO) expression with suppressed intraorgan triglycerides deposition, and importantly, protection against DKD. Conversely, exogenous SIRP alpha impaired kidney proximal tubular cell FAO, ATP production, and exacerbated fibrosis. Finally, suppressing SIRP alpha in skeletal muscles or treatment with anti-SIRP alpha monoclonal antibodies in STZ-treated mice mitigated cachexia, hyperlipidemia, kidney triglyceride deposition, and renal dysfunction in spite of significant hyperglycemia. Importantly, serum SIRP alpha was upregulated in patients with DKD. In conclusion, SIRP alpha serves as a potential biomarker and therapeutic target in DKD.