Protective Effects Of Melatonin On Diabetic Nephropathy And Its Mechanism Study

With the development of economics, people's life style has changed greatly and the prevalence rate of diabetes mellitus has rised so rapidly that it has become one of public problem that severely threaten the health of the people worldwide. Diabetic nephropathy has been the most principal cause of end-stage renal failure. Numerous factors have been recognized as contributing to the pathogenesis and progression of diabetic nephropathy. However, the exact mechanism of action is not clear. It has recently been proposed that oxidative stress plays an important role in the progression of diabetic chronic complicatons, many relevant experiments and clinical studies have been completed to confirm this concept. The current data provide evidence that reactive oxygen species (ROS) generated by glucose metabolism not only do harm to kidney directly, but also play an important role in signaling pathways acting as integral signaling molecules as in other membrane receptor signaling to modulate gene expression. So selecting appropriate antioxidant to alleviate the diabetic glomerular injury has important significance in clinical work.Melatonin is a hormone produced mainly by the pineal gland during the dark phase of the circadian cycle with typical circadian rhythm with maximal secretion at night and depression during the day. As one of the important neuro-endocrinology hormones, melatonin used to be thinked of as a hormone which mainly regulate the physiological rhythms such as diurnal rhythm and a seasonal rhythm in mammals. With the proceeding of melatonin study in recent years, many functions of melatonin were founded. The hormone plays a certain role in temperature regulation in mammals as well as in the onset of puberty and senescence. It regulates reproductive, cardiovascular gastrointestinal, respiratory as well as renal system and water and mineral metabolism. Melatonin also has immunoenhancing and antitumor effects. In the recent years, attention has been concentrated on the antioxidative effects whichare belived to be responsible for its antitumor, anti-aging effect. And it is believed that melatonin is the most effective lipophilic antioxidant so far. However, the exact mechanism of action of this high active hormone remains to be elucidated. Present study suggests that it mainly involves two sides: to neutralize free radical directly as electron donor; to reduce oxidative reaction indirectly by activating glutathione peroxidase and inhibiting nitricoxide synthase activity.In this study, we used several study techniques and methods to resolve the following questions: 1. to investigate the effect of melatonin on renal function and morphological changes in the kidneys of STZ-induced diabetic rats; 2. to clarify the effect of high glucose on rat mesangial cells proliferation and the intervention effect of melatonin; 3. to investigate the changes of TGP-P1 in the kidney of diabetic rats and mesangial cells cultured in high glucose and to reveal the effects of melatonin on the expression of TGF-1; 4. to elucidate the existence of oxidative stress in diabetic rats and mesangial cells cultured in media containing high glucose concentration and to demonstrate the antioxidative effects of melatonin.Main methods and results:The first part: Methods: Diabetes mellitus was induced in male SD rats (150-200mg ) by an intraperitoneal injection(45 mg/kg) of streptozotocin. Blood glucose levels were measured three days after the injection to ensure a diabetic state ( 16.7 mmol/L). Then diabetic rats were assigned to one of the following groups: i) diabetic control (DM), untreated; ii) DM+Meli, melatonin supplement by 0.2 mg.kg-1d-1, gavage; or iii) DM+Mel2, melatonin supplement by 5 mg.kg-1d-1, gavage. The treatment started 3 days after streptozotocin injection and continued for 8 weeks. Periodically, body weight, blood glucose, plasma triglyceride and plasma cholesterol levels were measured as clinical and biochemical parameters; plasma creatinine, glomerular filtration rate (creatinine clearance), urinary protei...