TLR4在进展期糖尿病肾病作用机制的研究

糖尿病肾病已成为终末期肾病（ESRD）的重要原因，许多研究表明炎症分子和免疫机制在糖尿病肾病的发生和发展中起重要作用。Toll受体4(TLR4)是介导天然免疫的古老分子，最近我们发现TLR4表达水平在糖尿病肾病患者肾脏中显著上调，并在糖尿病肾病肾小管炎症中发挥关键作用。本项目应用TLR4特异性拮抗剂研究TLR4通路在实验性进展期糖尿病肾病模型肾小球病变和肾间质纤维化中的作用机制，并初步探讨抑制TLR4通路对糖尿病肾病的肾脏保护作用。同时在体外建立肾小球病变和肾小管上皮纤维化模型，进一步从基因水平和信号传导水平深入研究TLR4在糖尿病肾病时肾小球细胞相互作用，炎症细胞浸润和肾间质纤维化中的作用。本研究将为阐述糖尿病肾病的发病机制提供新的方向，并为TLR4拮抗剂用于糖尿病肾病治疗提供一定的理论和实验依据。

Diabetic nephropathy (DN) is becoming one of the most important causes of end stage renal disease (ESRD)in China.Emerging evidence has shown that inflammatory elements play a key role in the development and progression of DN, therefore further investigation into the inflammatory and immunological mechanism will provide potential therapeutic target for DN. Toll-like receptors (TLRs) are fundamental elements in the innate immune system that trigger proinflammatory signaling pathways. We recently showed that Toll-like receptor 4 (TLR4) was overexpressed in the human diabetic kidney, which could promote tubular inflammation during diabetes. The current study aims to explore whether the TLR4 antagonist could have therapeutic potential to attenuate the renal injuries and slow the progression of advanced DN in animal model. Moreover, in vitro，the role of TLR4 signaling in the glomerular damages and tubulointerstial fibrosis will be examined by using cultured glomerular cells and tubular epithelial cell. This study will provide important insights into the mechanism of DN, and will render novel experimental evidence to determine the renoprotective effects of pharmacological inhibition of TLR4 in DN.