ANGPTL3通路在糖尿病视网膜病变发病中的作用

The main pathological features of diabetic retinopathy (DR) is a vascular leakage and neovascularization, but the mechanism is not completely clear. Recently, our group found that angiopoietin -like protein 3 (ANGPTL3) increased in the retina of diabetic rats, which regulates the expression of cytokines as well as blood lipids, and was positively correlated with the increased retinal vascular permeability , however, its effect is unknown. Therefore, by using recombinant DNA technology, this study is designed to, firstly, clarify the role of activation of ANGPTL3 mediated the increased apolipoprotein B induced by high glucose in the pathogenesis of DR; secondly explore whether ANGPTL3 activated binding with integrins αVβ3 caused PI3K/Akt pathway activation, which leads to the increased inflammatory cytokines, apoptotic factors and angiogenic factors, resulting in retinal vascular injury; further, reveal that ANGPTL3 may be an effective target for the treatment of DR through intervention study. In addition, this study observed association ANGPTL3 patients with diabetic retinopathy. So far, it is no report about the action of ANGPTL3 in the pathogenesis of DR. It is believed that the novel findings would highlight the potential role of ANGPTL3 in the pathogenesis of DR under condition of hyperglycemia and high cholesterol. In summary, these results may provide scientific basis for the prevention and treatment of DR.

糖尿病视网膜病变（DR）主要病理特征是血管渗出及新生血管形成，然而机制不完全清晰。最近，本课题组发现，有调节血脂和细胞因子表达作用的血管生成素样蛋白3（ANGPTL3）在糖尿病大鼠视网膜组织高表达，且与视网膜血管渗透性增加呈正相关，但作用不明。为此，本课题运用基因重组技术，首先阐明高糖状态下活化的ANGPTL3调节载脂蛋白B升高在DR发病中的作用；其次探讨活化的ANGPTL3与整合素αVβ3受体结合是否引起PI3K/Akt通路激活，炎症因子、凋亡因子及血管生成因子上调，导致视网膜血管损伤；进而以ANGPTL3为靶标进行干预，揭示ANGPTL3可能是DR治疗的有效靶点。此外，本课题还将观察ANGPTL3与糖尿病患者视网膜病变的关联性。迄今，这些研究在国际上尚属空白，其预期的研究结果可能丰富人们对高血糖及高血脂在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。

糖尿病视网膜病变（DR）主要病理特征是血管渗出及新生血管形成，然而机制不完全清晰。为此，本课题运用基因重组技术，探讨活化的ANGPTL3与整合素αVβ3受体结合是否引起PI3K/Akt通路激活，炎症因子、凋亡因子及血管生成因子上调，导致视网膜血管损伤；进而以ANGPTL3为靶标进行干预，揭示ANGPTL3可能是DR治疗的有效靶点。研究发现：（1）糖尿病性视网膜病变中，ANGPTL3表达水平增加，炎症和凋亡反应显著上升；（2）ANGPTL3 通过与整合素αVβ3受体相互作用介导视网膜组织细胞促炎、促凋亡反应，ANGPTL3是糖尿病性视网膜病变发生的重要干预靶点。（3）非诺贝特可抑制高糖诱导的ANGPTL3上调及整合素αVβ3活化，减少糖尿病视网膜组织细胞炎症和凋亡反应，抑制糖尿病性视网膜病变的发生。这些研究结果丰富了人们对高血糖在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。