Exercise alleviates diabetic kidney disease through PPAR��-CPT1�� pathway-dependent fatty acid ��-oxidation

Diabetic kidney disease (DKD), a severe diabetic complication affecting approximately one-third of diabetic patients, is the leading cause of end-stage chronic kidney disease. The benefits of regular exercise for patients with DKD have been well documented, particularly in overweight patients with DKD. However, the underlying mechanisms are incompletely understood. The present study demonstrates that exercise improves kidney function in diabetic db/db mice through activating PPAR��-mediated fatty acid ��-oxidation (FAO). Twelve-week treadmill running exercise improved kidney function in db/db mice. Metabolomics and transcriptomics profiling analysis collectively revealed that dysregulation of FAO in db/db mice was largely corrected by running exercise. KEGG pathway enrichment revealed that PPAR pathway, a critical signalling cascade in FAO and exercise, is involved in DKD, suggesting PPAR�� activation protects renal function through promoting FAO. Which was confirmed by improved renal function and enhanced FAO in db/db mice treated with PPAR�� agonist GW501516. Oppositely, PPAR��-specific inhibitor GSK0660 abolished exercise-mediated improvement in renal function and FAO. In combining with gene expression profiling data we identified CPT1��, the rate-limiting enzyme in fatty acid oxidation, was suppressed in the kidney of diabetic mice and reversed by exercise and the PPAR�� agonist GW501516. The findings hint at a potential role for the PPAR��-CPT1�� pathway in exercise-induced improvements in diabetic renal function and may warrant further exploration of the PPAR��-CPT1�� pathway as a therapeutic target in DKD.