SGLT2 inhibitor improves kidney function and morphology by regulating renal metabolism in mice with diabetic kidney disease

Background: Diabetic kidney disease (DKD) is a secondary complication of diabetes mellitus and a leading cause of chronic kidney disease. Aim: To investigate the impact of long-term canagliflozin treatment on DKD and elucidate its underlying mechanism. Methods: DKD model was established using high -fat diet and streptozotocin in male C57BL/6J mice (n = 30). Mice were divided into five groups and treated for 12 weeks. 1) normal control mice, 2) DKD model, 3) mice treated low -dose of canagliflozin, 4) high -dose of canagliflozin and 5) 13-hydroxybutyrate. Mice kidney morphology and function were evaluated, and a metabolomics analysis was performed. Results: Canagliflozin treatment reduced blood creatinine and urine nitrogen levels and improved systemic insulin sensitivity and glucose tolerance in diabetic mice. Additionally, a decrease in histological lesions including collagen and lipid deposition in the kidneys was observed. 13-hydroxybutyrate treatment did not yield a comparable outcome. The metabolomics analysis revealed that canagliflozin induced alterations in amino acid metabolism profiles in the renal tissue of diabetic mice. Conclusion: Canagliflozin protects the kidneys of diabetic mice by increasing the levels of essential amino acids, promoting mitochondrial homeostasis, mitigating oxidative stress, and stimulating the amino acid -dependent tricarboxylic acid cycle.