基于EZH2调节的NLRP3炎症小体通路研究尿酸在糖尿病视网膜病变发病中的作用

Uric acid is an independent risk factor for the pathogenesis of diabetic retinopathy (DR). Recently, we found that postoperative vitreous hemorrhage in proliferative DR (PDR) with hyperuricemia was more than that in PDR without hyperuricemia, and urinary acid induced EZH2 expression decreased, NLRP3 inflammasome activation, and apoptosis increased in retinal vascular endothelial cells. However, its mechanism is unknown. Therefore, by using recombinant DNA technology, ChIP, and mDIP, this study is designed to, firstly, clarify EZH2 might induce NLRP3 inflammasome activation through regulating histone H3K27 methylation and DNA methylation decreased in diabetic retinal tissue and vascular endothelial cells by uric acid; Secondly, explore whether the activation of NLRP3 inflammasome cause the up-regulation of inflammation factor, apoptosis factor and angiogenesis factor, leading to DR; further, reveal that EZH2 may be an effective target for the treatment of DR through intervention study. In addition, it is aimed to study whether serum uric acid is a mark for postoperative vitreous hemorrhage in severe PDR. So far, it is no report about the action of EZH2-regulated NLRP3 inflammasome pathway in the pathogenesis of DR. It is believed that the novel findings would highlight the potential role of uric acid in the pathogenesis of DR induced by uric acid. In summary, these results may provide scientific basis for the prevention and treatment of DR.

尿酸是糖尿病视网膜病变（DR）发病的一个独立危险因子。最近，本课题组发现，高尿酸血症增殖性DR（PDR）患者术后玻璃体再出血显著高于血尿酸水平正常者；尿酸诱导视网膜血管内皮细胞EZH2表达降低，NLRP3炎症小体活化及细胞凋亡增加，但其机制不明。为此，本课题运用基因重组、ChIP、mDIP等技术，首先阐明尿酸可能诱导糖尿病视网膜组织细胞EZH2调节的组蛋白H3K27甲基化和DNA甲基化降低，NLRP3炎症小体激活；其次探讨NLRP3炎症小体活化是否引起炎症因子、凋亡因子及血管生成因子上调导致DR；进而以EZH2为靶标进行干预，揭示EZH2可能是DR治疗有效靶点。此外，本课题还将研究血清尿酸作为严重PDR玻璃体手术后玻璃体再出血一个预测指标的可行性。迄今，这些研究在国际上尚属空白，预期的研究结果可能丰富人们对尿酸在DR发生机制的认识，为DR临床防治提供理论和实验依据，具有重要理论和现实意义。

尿酸是糖尿病视网膜病变（DR）发病的一个独立危险因子，然而其机制不完全清晰，本课题应用基因重组等技术，探讨尿酸是否参与了糖尿病视网膜病变的发生发展，并探究了尿酸促进糖尿病视网膜组织炎症水平、凋亡事件增多的分子机制；进而以尿酸水平为靶标进行干预，揭示控制血清尿素水平可能是DR治疗的有效靶点。.研究发现：（1）高水平血清尿酸与2型糖尿病患者发生威胁视力的糖尿病视网膜病变（VTDR）风险增加相关；（2）高尿酸上调T2DM小鼠视网膜组织EZH2水平，诱发T2DM模型小鼠视网膜感光细胞损伤，外节段层消失，视网膜变薄；（3）高糖合并高尿酸通过激活Notch信号通路促进DR视网膜组织凋亡及炎症反应，沉默Notch-1可下调视网膜凋亡水平及炎症反应。这些研究结果丰富了人们对尿酸在DR发生机制的认识，为DR临床防治提供理论和实验依据，具有重要的理论和现实意义。