# Myokine SIRPα exacerbates kidney disease in diabetes

## TL;DR

The myokine SIRPα worsens kidney disease in diabetes by impairing fatty acid oxidation and promoting fibrosis.

## Contribution

This study identifies SIRPα as a novel myokine involved in diabetic kidney disease progression.

## Key findings

- Genetic deletion of muscle SIRPα protects against obesity and improves insulin signaling.
- Exogenous SIRPα impairs kidney proximal tubular cell function and exacerbates fibrosis.
- Anti-SIRPα treatment mitigates kidney dysfunction and triglyceride deposition in diabetic mice.

## 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.

Myokine SIRPα inhibits kidney proximal tubule fatty acid (FA) oxidation while promoting diabetic kidney disease.