1.1类新药硝克柳胺通过干扰AGE-RAGE信号通路对慢性肾功能不全的治疗作用机制研究

晚期糖基化产物（AGE）通过和其受体（RAGE）结合、激发下游信号通路是引发包括糖尿病肾病在内多种慢性肾功能不全的主要原因之一。我所自主研发的1.1 类新药硝克柳胺，临床前药效学研究已经证实它对于多种慢性肾病有着良好疗效，目前该药正在申报Ⅱ期临床试验。前期研究表明硝克柳胺能够有效抑制由AGE 引起的大鼠外周血和肾组织中TGFβ1 和结缔组织生长因子（CTGF)的分泌，但是对于硝克柳胺是否直接作用于AGE-RAGE信号通路，尚缺乏充足的研究证据。本课题目的在于借助体内、体外模型研究硝克柳胺是否可以抑制肾损伤状态下RAGE在足细胞、肾小球内皮细胞和间质细胞中的表达，能否抑制AGE-RAGE激活后引发的下游炎症和氧化应激反应、对足细胞是否有保护作用。同时利用先进的表面等离子共振技术（SPR），研究硝克柳胺是否与RAGE存在直接相互作用，旨在进一步深入阐明1.1类新药硝克柳胺的肾保护作用分子机理。

Advanced glycation end products (AGEs) interacting with its receptor (RAGE) plays an important role in the pathogenesis of chronic renal dysfunction, which could be caused by diabetic nephropathy, hypertension and so on. Activation of AGE-RAGE signal pathway can stimulate the expressions of fibrogenic transforming growth factor (TGF-β1) and connective tissue growth factor (CTGF), which in turn induce renal hypertrophy, sclerosis and functional failure. Nicousamide, a novel class 1.1 medicine and a coumarin-aspirin derivative was demonstrated to inhibit AGEs formation and crosslink and prevent diabetic nephropathy in streptozotocin-induced diabetic rats, which is now undergoing Phase- Ⅱ clinical evaluation. However, the detailed mechanism about how this small molecular compound interferes the AGE-RAGE pathway is not clear. This project aims to use surface plasmon resonance(SPR) technique to analyze the interaction between nicousamide and glucose, proteins and AGEs, try to understand how nicousamide inhibits the AGEs formation and block the AGEs-protein crosslink. Meanwhile, we will investigate whether nicousamide can inhibit expression of receptor of AGEs and inactivate RAGE's activity. One in all, this project will help us to understand further pharmacological mechanism of nicousamide.