Abstract
Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-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-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα 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, mSIRPα-KO mice displayed enhanced kidney tubular fatty acid oxidation (FAO) expression with suppressed intraorgan triglycerides deposition, and importantly, protection against DKD. Conversely, exogenous SIRPα impaired kidney proximal tubular cell FAO, ATP production, and exacerbated fibrosis. Finally, suppressing SIRPα in skeletal muscles or treatment with anti-SIRPα monoclonal antibodies in STZ-treated mice mitigated cachexia, hyperlipidemia, kidney triglyceride deposition, and renal dysfunction in spite of significant hyperglycemia. Importantly, serum SIRPα was upregulated in patients with DKD. In conclusion, SIRPα serves as a potential biomarker and therapeutic target in DKD.
Authors
Jiao Wu, Elisa Russo, Daniela Verzola, Qingtian Li, Helena Zhang, Bhuvaneswari Krishnan, David Sheikh-Hamad, Zhaoyong Hu, William E. Mitch, Sandhya S. Thomas
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