The Prevention Effect Of Zinc On Diabetic Retinopathy

Zinc is one of trace elements, widely exists in the nature. It is an important nutrient in the human body, and involved in homeostasis, immune responses, oxidative stress, apoptosis, and aging. Some studies have reported that zinc can increase antioxidants. For instance, Zn can induce metallothionein (MT) and Cu/Zn-SOD and also stabilize nuclear factor erythroid-2related factor2(Nrf2) to up-regulate its downstream antioxidant genes, NADPH quinine oxidoreductase1(NQO1), heme oxygenase-1(HO-1), catalase.Diabetes mellitus is a chronic disease with high morbidity and mortality, serious effects on human’s quality of life. With developed, a lot of serious complications appeared. These complications are divided into two groups, macrovascular complications, which include coronary artery disease, atherosclerosis, microvascular complications, which include cardiovascular diseases, nephropathy, and retinopathy. Increasing evidence indicates that increased oxidative stress is the major risk factor responsible for the development and progression of vascular complications in diabetic patients. It is well known that diabetes induced increases in blood glucose and metabolic disorders. The latter in turn induces increases in inflammatory response, reactive oxygen or nitrogen species (ROS or RNS), and oxidative stress and damage. These could impair target organs or tissues of diabetes, especially vascular endothelial cells, cause damage, such as inflammation, fibrosis, and apoptosis. Epidemiological studies have shown that plasma zinc concentrations and the Zn/Cu ratio were lower in diabetic subjects. Zinc supplement recovers it, and protects against oxidative changes in the early stages of diabetes. To these ends, present projects aimed to define whether zinc have the protective effect on diabetic macrovascular complications (such as aorta), diabetic microvascular complications (such as retina), and the probable mechanism.First, we tested the pathological change of retina in the mice with metabolic syndrome induced by high-fat-diet for6months. High-fat-diet-fed mice showed the pathological damage, such as inflammation, oxidative stress, and new angiogenesis in the retina. By the dynamic analysis, we found that the early inflammation and oxidative damage occur predominantly in and around the vessels. These results suggested that vascular damage may be the initial signals for the pathogenesis of diabetic retinopathy. Base on this, a genetic type I diabetic OVE26mouse model was used with/without zinc supplementation for3months. Diabetes significantly induced vascular damage in the diabetes group, but not in the zinc supplement diabetes group. The protective effect of zinc on diabetes-induced vascular damage was independent of animal genders. The vascular protection by zinc against diabetes-induced pathogenic changes is associated with the up-regulation of both MT and Nrf2expression. Nrf2is an important nuclear transcription factor that plays a critical role in orchestral regulation of oxidative and antioxidative balance, so we further discussed the prevention and therapeutic effect of Nrf2. Two different diabetic models were used:STZ mice model and OVE26mice model, with and without sulforaphane (SFN) and MG132(proteasome inhibitor) since both SFN and MG132could induce Nrf2expression. SFN showed the strong prevention of diabetic induction of vascular damage with up-regulation of vascular Nrf2expression and transcription, which could observed not only at the end of the treatment, but also at3months after stopping SFN treatment. Chronic treatment with low-dose MG132can afford a significantly therapeutic effect on diabetes-induced pathogenic changes in the vascular, which is associated with the increased Nrf2expression and function, even so exhibit albuminuria with increase in inflammatory response and oxidative damage in the vascular when treatment beginning. Taken together we have demonstrated that there are preventive and therapeutic effects on diabetes-induced vascular damage with up-regulated Nrf2expression and function.In summary, we have used the immunostaining, real-time PCR, and Western blotting assays with multiple mice models to investigate the pathogenesis of diabetic retinopathy and its possible intervention. Our results demonstrated that vascular oxidative damage is the initial pathogenic event in the early stage of diabetic retinopathy. Zinc supplementation had the prevention effect on diabetes induced vascular damage, which is associated with the increased Nrf2expression and transcription. This study will provide a new method for the prevention and treatment of diabetic complications; this also can provide important experimental and theoretical evidence for the prevention and treatment of zinc on diabetic retinopathy.