Txnip的DNA甲基化修饰在糖尿病肾病足细胞损伤中的作用及调控机制研究

The oxidative damage of podocyte is implicated to play a pivotal role in the development of diabetic nephropathy. This increased oxidative stress causes the activation of several major pathways involved in the pathogenesis of diabetic nephropathy, such as polyol pathway flux, increased formation of AGEs (advanced glycation end products), activation of protein kinase C isoforms and overactivity of the hexosamine pathway. Our preliminary studies demonstrated that Txnip (thioredoxin interacting protein) was one of the most abundantly up-regulated genes in response to hyperglycemia in podocyte. Piles of studies have confirmed that over-expression of Txnip induces intracellular oxidative stress and causes cell death. We also found out that hyperglycemia-induced oxidative stress and apoptosis could be prevented by silencing Txnip in podocyte. Moreover, the up-regulated Txnip in high glucose environment was correlated with decreased genomic methylation. Based on these findings, we assume that DNA methylation may regulate the expression of Txnip in podocyte. In the next work, we'll study the regulation of Txnip on podocyte oxidative injury, apoptosis and figure out the mechanism of increased Txnip by high glucose conditions via DNA methylation. By establishing a new pathway of “high glucose-DNA-demethylation-Txnip-podocyte injury-diabetic nephropathy”, our study may present potentially targets for the prevention and treatment of diabetic nephropathy.

足细胞的氧化损伤被认为是启动糖尿病肾病发病的关键环节。氧化应激发生后多条途径被激活最终导致足细胞凋亡、疾病发生，至今仍未能找到一个有效的上游靶标用于治疗。我们的前期研究首次发现Txnip（硫氧还结合蛋白）是高糖刺激下足细胞表达升高最显著的基因；高表达的Txnip将导致细胞氧化损伤进而促进细胞凋亡。用siRNA沉默足细胞中Txnip的表达，高糖诱导的氧化应激和凋亡都得到明显的改善；进一步的研究表明高糖环境下Txnip的高表达与DNA甲基化水平下调有关，提示DNA的甲基化修饰可能是高糖调控Txnip表达的重要途径。本课题旨在探索“高糖-DNA甲基化修饰-Txnip-足细胞氧化损伤-糖尿病肾病”的新通路，阐明高糖下调DNA的甲基化水平，促进Txnip的表达，导致足细胞氧化损伤、凋亡的机制。证明通过DNA甲基化修饰抑制Txnip表达或预防糖尿病肾病的发生，为治疗糖尿病肾病提供新的靶点和思路。

足细胞的氧化损伤被认为是启动糖尿病肾病发病的关键环节。氧化应激发生后多条途径被激活最终导致足细胞凋亡、疾病发生。我们的研究发现Txnip(硫氧还结合蛋白)是高糖刺激下足细胞表达升高最显著的基因;高表达的Txnip将导致细胞氧化损伤进而促进细胞凋亡。用siRNA沉默足细胞中Txnip的表达，高糖诱导的氧化应激和凋亡都得到明显的改善;进一步的研究表明高糖环境下Txnip的高表达与DNA甲基化水平下调有关，提示DNA的甲基化修饰可能是高糖调控Txnip表达的重要途径。此外，我们研究了恩格列净肾脏保护作用的机制，发现恩格列净可通过抑制Txnip的表达，进而抑制肾脏氧化应激途径而实现肾脏保护。为治疗糖尿病肾病提供新的靶点和思路。