Abstract: Objective To explore the mechanisms mediating the protective effect of carnosine against nephropathy in rats with diabetes mellitus (DM). Methods Rat models of DM established by high-fat diet feeding and streptozotocin injection were randomized into DM group and 3 treatment groups with daily carnosine treatment at 100, 300, and 900 mg/kg. Body weight and blood glucose level changes of the rats were measured regularly. After the treatment, 24-h urine, serum samples and kidneys of the rats were collected to measure urine volume, urine protein content, blood creatinine, and kidney mass; renal pathology was observed using HE staining, and MDA content and SOD activity in the kidney tissues were detected. Western blotting was performed to detect the protein expressions of p-AKT, AKT, p-mTOR, mTOR, LC3 and p62 in the kidney tissues. Results Compared with normal control rats, the diabetic rats exhibited dull and wet hair and showed decreased body weight, increased blood glucose, urinary protein content, 24-h urine volume, blood creatinine, and kidney mass with obvious swelling and deformation of the glomeruli, narrowing of the renal tubules, decreased SOD activity and increased MDA content, lowered p-mTOR/mTOR and p-AKT/AKT ratios and increased LC3 II/I ratio and p62 protein expression in the kidney tissue. The diabetic rats receiving carnosine treatments had dry hair with normal luster and showed increased body weight and slightly decreased blood glucose, urinary protein content, 24-h urine volume, blood creatinine, and kidney mass. The treatment also improved renal pathology, increased SOD activity, decreased MDA content, increased p-mTOR/mTOR and p-AKT/AKT ratios and lowered LC3 II/I ratio and p62 protein expression in renal tissue of the diabetic rats. Conclusion Carnosine offers protection against nephropathy in rats with DM possibly by inhibiting oxidative stress, activating the AKT/mTOR pathway, and restoring autophagy in the kidneys.

Key words: carnosine; diabetic kidney disease; autophagy; AKT; mTOR