锌诱导Nrf2参与糖尿病肾病氧化损伤及炎症的保护

The accumulation of mesangial extracellular matrix is the basic pathologic performance in diabetic nephropathy.The increasing of inflammation, oxidative damage and the imbalance of extracellular matrix synthesis and degradation, induced by hyperglycemia and hyperlipidemia in diabetes, were considered to be possible mechanism to lead to matrix accumulation. Zinc, as one of the trace elements, involves in a various of biological function,such as anti-inflammatory, anti-oxidation and promoting the mesangial matrix degradation.In diabetes, zinc loses through urine and can not to be absorpted sufficiently by gastrointestin, which cause zinc deficiency. We also have confirmed that zinc deficiency can enhance the oxidative damage, inflammation, and fibrosis in diabetic nephropathy. Furthermore, Nrf2 recently is considered to be an important antioxidant regulator, and might be involved in the protection of zinc to oxidative damage in diabetic nephropathy. Therefore, we make the hypothesis that zinc lessen the oxidative damage induced by hyperglycemia and hyperlipidemia in diabetes,and the possible mechanism is regulate the expression of Nrf2.In this project,the different concentration of zinc diet are feed to normal and STZ-induce diabetic mice. The level of oxidative damage, inflammation and fibrosis will be detected in order to know the protection of zinc in diabetic nephropathy.At the same time, some antioxidant factors are also to be detected because the expression of them are related with zinc.To know the possible molecular mechanism of zinc antioxidation,we make the in vitro experiment. Human renal proximal tubule cells are treated by high glucose and palmitate.TPEN is the special chelator of zinc and is used to low the intracellular concentration of zinc.SiRNA of Nrf2 will be applied to confirm the relation of zinc and Nrf2 in diabetic nephropathy. Moreover, we design a zinc supplementation experiment in different development stage of diabetic nephropathy, in order to know the best time of zinc supplementation to prevent occurrence and development of diabetic nephropathy.

肾小球系膜细胞外基质积聚为糖尿病肾病（DN）主要病理基础。其主要原因为糖尿病时高糖高脂血症诱导的炎症、氧化损伤及肾小球系膜外基质成分合成和降解失衡。锌作为机体必需微量金属元素，参与抗炎、抗氧化及促进肾小球系膜外基质降解等生物过程。糖尿病时，尿锌增加及胃肠道吸收减弱，多存在低锌血症。我们已证实锌缺乏加重氧化损伤、炎症及纤维化。Nrf2作为重要的抗氧化因子调节剂，可能参与锌对DN氧化损伤的保护作用。因此我们推断锌可能通过Nrf2降低DN时氧化损伤。本课题应用低、高及正常含量锌饮食喂养1型糖尿病小鼠模型，观察其氧化损伤、炎症及纤维化的变化，同时了解锌诱导相关抗氧化剂表达，确定锌与DN关系；应用高糖高脂低锌肾小球系膜细胞模型，研究锌保护糖尿病肾病的可能分子机制及与Nrf2的关系；在DN发展不同阶段给予实验动物补锌，观察锌对不同阶段糖尿病肾病的治疗作用，为临床应用锌预防及治疗DN提供实验及理论依据。

肾小球系膜细胞外基质积聚为糖尿病肾病（DN）主要病理基础。其主要原因为糖尿病时高糖高脂血症诱导的炎症、氧化损伤及肾小球系膜外基质成分合成和降解失衡。锌作为机体必需微量金属元素，参与抗炎、抗氧化及促进肾小球系膜外基质降解等生物过程。糖尿病时，尿锌增加及胃肠道吸收减弱，多存在低锌血症。我们已经证实锌缺乏加重氧化损伤、炎症及纤维化。Nrf2作为重要的抗氧化因子调节剂，可能参与锌对DN氧化损伤的保护作用。因此我们推断锌可能通过Nrf2降低DN时氧化损伤。本课题应用低、高及正常含量锌饮食喂养1型糖尿病小鼠模型，观察其氧化损伤、炎症及纤维化的变化，同时了解锌诱导相关抗氧化剂表达，确定锌与DN的关系及其相关机制的研究，为临床应用锌预防及治疗DN提供实验及理论依据。