SIRPα Neutralization Reverses Kidney Lipid Metabolism Defects, Improving Kidney Function Despite Hyperglycemia in Type 1 Diabetes

Background: Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that SIRPα, a circulating mediator, impairs intracellular insulin-mediated functions. To determine insulin-independent effects on kidney fatty acid oxidation, a model of significant hyperglycemia was utilized, streptozotocin (STZ), an insulinopenic model. Methods: To elucidate the impact of myokine SIRPα on diabetic kidney disease (DKD), a model of significant hyperglycemia was utilized, streptozotocin (STZ), an insulinopenic model. Three groups of mice (fl/fl, mSIRPα-/-, or anti-SIRPα monoclonal antibody (mAb)-treated fl/fl mice) were treated with STZ to induce significant hyperglycemia. Methods of evaluation include qPCR, immunohistochemistry, with sirius red staining and serum measurements. Results: Suppressing SIRPα in skeletal muscles or treatment with anti-SIRPα monoclonal antibodies in STZ-treated mice, mitigated cachexia, proteinuria, polyuria, when compared to flox STZ-treated mice. Next, serum and kidney triglyceride, total cholesterol, lipid deposition, glomerular size, and importantly serum creatinine were found to be significantly reduced in STZ-treated mSIRPα-/- or anti-SIRPα-fl/fl mice. Additionally, STZ was found to suppress renal FAO transcripts with upregulation of genes encoding fibrosis in STZ-treated fl/fl mice vs. their respective control mice. In fact, FAO was found to be improved in mSIRPα-/-, or anti-SIRPα mAb-treated mice when comparing with fl/fl mice after STZ treatment. Conclusion: In conclusion, blocking SIRPα improved kidney fatty acid metabolism and prevented diabetic kidney damage. Therefore, SIRPα serves as a novel biomarker and therapeutic target in diabetic kidney disease. Funding: Veterans Affairs Support