SIRT1/FOXO1通路对糖尿病肾病足细胞线粒体氧化应激损伤的影响机制及桑枝多糖的干预研究

Podocyte damage is one of crucial factors in the pathogenesis of Diabetic Nephropathy (DN). The SIRT1/FOXO1 signal pathway could be a potential therapeutic target for the mitochondrial oxidative and podocyte damage. We discovered that the RMP not only reduce the inflammatory response of DN, but also improve the activity of MnSOD, down regulated the expression of MDA and Cyto-C. Besides, the expression of Nephrin and FOXO1 in renal were also increased. Therefore we reckon that the renal protective effect of RMP may be related to its activation of SIRT1/FOXO1 signal pathway. We intend to use the SRT1720 activate SIRT1, EX527 inhibit SIRT1, and siRNA for FOXO1 silencing for high glucose induced podocyte in vitro, and using mice induced by STZ as a model of DN in vivo, giving different doses of RMP. We observe the oxidative stress level of mitochondria, the function of podocyte and the condition of renal, discussing the effect of SIRT1/FOXO1 pathway as well as its downstream genes in mitochondrial oxidative and podocyte damage. The aim of this study was to determine the relationship and underlying mechanisms between RMP and DN, that will provide an experimental basis for further mechanism research via SIRT1/FOXO1 on RMP, and that would be useful to make clear the function of SIRT1/FOXO1 in improving DN and provide new strategies for its drug research.

足细胞损伤是糖尿病肾病（DN）发病的一个关键因素。能调控线粒体氧化应激损伤的SIRT1/FOXO1信号通路可能是其新的有效干预靶标。我们发现桑枝多糖（RMP）在改善DN肾脏炎症损伤的同时，可以提高肾皮质MnSOD活性，降低MDA及Cyto-C，上调Nephrin及FOXO1表达，推测RMP的DN肾脏保护机制可能与其激活SIRT1/FOXO1通路有关。本项目拟以SIRT1激动剂SRT1720和抑制剂EX527、siRNA沉默FOXO1技术分别干预高糖刺激体外培养的足细胞，并建立STZ诱导的小鼠为DN体内模型，均予不同剂量RMP干预，观察线粒体氧化应激水平、足细胞损伤情况及肾功能变化情况，验证SIRT1/FOXO1及其下游因子在DN足细胞线粒体氧化应激损伤机制中的作用。为探寻RMP抗DN机制的靶标提供实验依据，同时为探索DN针对性防治措施及药物研究提供新靶标及新策略。

足细胞损伤是糖尿病肾病(DN)发病的一个关键因素。能调控线粒体氧化应激损伤的SIRT 1/FOXO1信号通路可能是其新的有效干预靶标。我们从桑叶中提取出桑枝多糖(RMP)，发现其在改善DN肾脏炎症损伤的同时，可以提高肾皮质MnSOD活性，降低MDA及Cyto-C，上调Nephrin及FOXO1表达，并且RMP的DN肾脏保护机制与其激活SIRT1/FOXO1通路有关。本项目以SIRT1激动剂SRT1720和抑 制剂EX527、siRNA沉默FOXO1技术分别干预高糖刺激体外培养的足细胞，并建立STZ诱导的小鼠 为DN体内模型，均予不同剂量RMP干预，观察线粒体氧化应激水平、足细胞损伤情况及肾功能 变化情况，验证SIRT1/FOXO1及其下游因子在DN足细胞线粒体氧化应激损伤机制中的作用。为探寻RMP抗DN机制的靶标提供实验依据，同时为探索DN针对性防治措施及药物研究提供新靶标及新策略。