糖尿病肾病足细胞胰岛素抵抗的相关机制研究

In the glomerular inherent cells, some studies found that podocytes were the target cells of insulin. In diabetes, the occurrence and development of diabetic nephropathy (DN) is related with podocyte insulin resistance, but the mechanism is still unclear. Our previous studies have shown that insulin resistance and oxidative stress were closely related, while the nuclear factor erythroid -2p45 related factor 2 (Nrf2) and microRNA-144 (miRNA-144) played important roles in both oxidative stress and insulin resistance. Therefore, the project through the establishment of glomerular podocytes culture and diabetic nephropathy animal model with insulin resistance in high concentrations of glucose and lipid, to research the relationship between oxidative stress and podocytes insulin resistance in diabetes, and analyze the effects of miRNA-144 and Nrf2 in this relationship and its mechanism. The content including: (1) the relationship between oxidative stress and podocyte insulin resistance in high concentrations of glucose and lipid,; (2) the expression of Nrf2 is associated with the oxidative stress-induced insulin resistance in podocytes in high glucose and lipid, while in which the role of miRNA-144 and its mechanism; (3) the effect of atorvastatin on podocyte insulin resistance in high glucose and lipid and the possible mechanism. Our study will provide new ideas for prevention and treatment of DN.

研究发现足细胞是胰岛素作用的靶细胞。糖尿病时，足细胞胰岛素抵抗与糖尿病肾病（DN）的发生发展有关，具体机制尚不明。课题组前期研究表明胰岛素抵抗与氧化应激关系密切，且转录因子红细胞系-2p45相关因子-2（Nrf2）与微小RNA-144（miRNA-144）在氧化应激和胰岛素抵抗中均起重要作用。因此，本项目通过建立高糖高脂环境下胰岛素抵抗的足细胞培养和DN动物模型，研究糖尿病中氧化应激和足细胞胰岛素抵抗的关系，同时探讨miRNA-144和Nrf2在此相互关系中所起的作用及其可能机制。内容包括：1.高糖高脂环境下氧化应激与足细胞胰岛素抵抗的相互关系；2.高糖高脂培养条件下，氧化应激诱导的足细胞胰岛素抵抗是否与Nrf2表达变化相关，同时miRNA-144在其中所起的作用及具体机制；3.高糖高脂培养条件下阿托伐他汀对足细胞胰岛素抵抗的影响及其可能机制。通过以上研究，以期为DN的防治提供新的思路。

足细胞胰岛素抵抗与DN的发生发展有关，具体机制尚不明确。转录因子红细胞系-2p45相关因子-2（Nrf2）与微小RNA-144（miRNA-144）在氧化应激和胰岛素抵抗中均起重要作用，但在其中发挥作用的具体机制尚不明确。本项目通过建立足细胞胰岛素抵抗和DN动物模型，研究氧化应激诱导的足细胞胰岛素抵抗是否与 microRNA-144 对 Nrf2 的调控相关。主要内容包括：1.高糖高脂环境下氧化应激与足细胞胰岛素抵抗的相互关系；2.高糖高脂培养条件下，氧化应激诱导的足细胞胰岛素抵抗是否与Nrf2 表达变化相关，同时miRNA-144在其中所起的作用及具体机制；3.高糖高脂培养条件下阿托伐他汀对足细胞胰岛素抵抗的影响及其可能机制。结果显示，高糖可诱导足细胞损伤，NRF2表达下降，氧化应激增加，足细胞胰岛素敏感性下降，通过过表达NRF2以及抑制miR-144表达证实，高糖诱导的足细胞氧化应激和胰岛素抵抗与miR-144对NRF2的调控有关；阿托伐他汀在体内和体外均可改善氧化应激和足细胞胰岛素抵抗，通过调控miR-144/NRF2 发挥DN保护作用，为糖尿病肾病的防治提供新的思路。