Investigation of the nitric oxide signaling pathway induced by ezetimibe on renal injury in streptozotocin-induced diabetic rat: role of anti-oxidative and anti-inflammatory effects.

INTRODUCTION: Diabetes is a disease characterized by impaired insulin secretion and/or function. Ezetimibe is a lipid-lowering drug widely used for the treatment of hypercholesterolemia. This study investigates the impact of ezetimibe on nitric oxide level and its effects on diabetic nephropathy. MATERIALS & METHODS: Sixty rats were used in the study, divided into the following groups: a control group (healthy rats), a diabetic control group, a diabetic group treated with metformin, a diabetic group treated with ezetimibe, a diabetic group treated with ezetimibe plus L-NAME, and a diabetic group treated with ezetimibe plus L-arginine. After 28 days, blood samples were collected and rats were euthanized to examine nitric oxide levels and kidney histology. The levels of creatinine, urea, glutathione peroxidase (GPx), catalase (CAT), tumor necrosis factor (TNF-α), and interleukin (IL-6) were measured. RESULTS: Ezetimibe treatment resulted in decreased levels of urea and creatinine in blood samples, along with reduced TNF-α and IL-6 levels in the kidneys. Additionally, GPx and CAT levels significantly increased following ezetimibe treatment. Our findings showed that the combination of ezetimibe and L-arginine provided protection against nephropathy in the animals, as demonstrated by enhanced antioxidant activity and reduced inflammation. However, the beneficial effects of ezetimibe were reversed by L-NAME. CONCLUSION: Ezetimibe protected the kidney against diabetic injury mainly by activating the nitric oxide signaling pathway, enhancing antioxidant enzyme activity, and reducing inflammation, suggesting that its nephroprotective effects are NO-dependent.