Myokine SIRPα exacerbates kidney disease in diabetes.

Summary

This mechanistic study identifies skeletal muscle–derived SIRPα as a circulating mediator that worsens diabetic kidney disease by impairing proximal tubule fatty acid oxidation and promoting fibrosis. Muscle-specific SIRPα deletion and anti-SIRPα monoclonal antibodies protected mice from DKD features despite persistent hyperglycemia, and serum SIRPα was elevated in patients with DKD.

Key Findings

• Serum SIRPα increased in obesity-induced diabetic mice and in patients with DKD.
• Muscle-specific SIRPα knockout protected against obesity, improved insulin signaling, enhanced tubular FAO, reduced renal triglyceride deposition, and mitigated DKD.
• Exogenous SIRPα impaired proximal tubular FAO and ATP production and exacerbated renal fibrosis.
• Anti-SIRPα monoclonal antibodies improved cachexia, hyperlipidemia, renal lipid deposition, and kidney dysfunction in STZ-diabetic mice despite hyperglycemia.

Clinical Implications

If validated in humans, SIRPα could serve as a biomarker to identify DKD risk and a therapeutic target to protect kidneys independently of glycemic control. This may enable adjunctive therapies for patients with progressive DKD.

Limitations

• Preclinical study; efficacy and safety of anti-SIRPα therapy in humans remain unknown.
• The receptor/uptake mechanisms for circulating SIRPα in renal tubules require clarification.

Future Directions

Define renal targets/receptors of SIRPα, validate SIRPα as a prognostic biomarker in prospective human cohorts, and initiate early-phase trials of anti-SIRPα in DKD.