Fenofibrate Exerts Protective Effects in Diabetic Retinopathy via Inhibition of the ANGPTL3 Pathway.
Fenofibrate Exerts Protective Effects in Diabetic Retinopathy via Inhibition of the ANGPTL3 Pathway.
复制标题
DOI：
10.1167/iovs.18-24155
复制
发表时间：
2018-08
影响因子：
4.4
通讯作者：
Na Wang;Chen Zou;Shu-zhi Zhao;Yunzhi Wang;Changjing Han;Zhi Zheng
中科院分区：
文献类型：
--
作者：
Na Wang;Chen Zou;Shu-zhi Zhao;Yunzhi Wang;Changjing Han;Zhi Zheng
目的 非诺贝特已被证明对糖尿病视网膜病变具有良好的治疗效果。血管生成素样 3 (ANGPTL3) 已被证明对血管内皮细胞产生显着的致病作用，而血管内皮细胞在糖尿病视网膜病变的发病机制中发挥着重要作用。本研究旨在探讨非诺贝特在糖尿病视网膜病变中的治疗作用与 ANGPTL3 的致病作用之间的联系。方法糖尿病大鼠和对照大鼠被随机分配接受以下治疗：玻璃体内注射ANGPTL3小干扰RNA（siRNA）、重组人（rh）ANGPTL3，用正常饲料或含非诺贝特的饲料喂养8周。通过 ANGPTL3 siRNA、ANGPTL3 RNA 过表达、空白载体、西仑吉肽或非诺贝特治疗，将人视网膜微血管内皮细胞 (HRMEC) 暴露于正常葡萄糖或高葡萄糖水平。通过Western blotting和实时PCR检测大鼠视网膜和HRMECs中ANGPTL3、IL-1、IL-6、Bax、P53、VEGF和整合素αVβ3的表达水平。使用TUNEL细胞凋亡检测试剂盒检测HRMEC的细胞凋亡率。结果HRMECs或糖尿病视网膜组织中ANGPTL3、IL-1β、IL-6、Bax、P53、VEGF和整合素αVβ3的表达水平在高糖刺激或ANGPTL3过表达后上调。然而，在非诺贝特干预、整合素αVβ3受体阻断或ANGPTL3 siRNA干扰后，上述标志物的表达水平下调。结论 我们发现非诺贝特通过抑制 ANGPTL3 诱导的糖尿病视网膜病变细胞凋亡和炎症发挥保护作用，这是一种新机制。
Purpose Fenofibrate has been demonstrated to exert a promising therapeutic effect against diabetic retinopathy. Angiopoietin-like 3 (ANGPTL3) has been shown to exert significant pathogenic effects on vascular endothelial cells, which are critically involved in the pathogenesis of diabetic retinopathy. The present study aimed to investigate the link between the therapeutic effects of fenofibrate and the pathogenic effects of ANGPTL3 in diabetic retinopathy. Methods Diabetic and control rats were randomly assigned to the following treatments: intravitreal injection with ANGPTL3 small interfering RNA (siRNA), recombinant human (rh)ANGPTL3, fed with normal feeds, or fenofibrate-containing feeds for 8 weeks. Human retinal microvascular endothelial cells (HRMECs) were exposed to normal glucose or high glucose levels with ANGPTL3 siRNA, ANGPTL3 RNA overexpression, blank vector, cilengitide, or fenofibrate treatment. Expression levels of ANGPTL3, IL-1, IL-6, Bax, P53, VEGF, and integrin αVβ3 in the retinas of rats and HRMECs were examined by Western blotting and real-time PCR. The apoptosis rates of HRMECs were examined using a TUNEL apoptosis assay kit. Results Expression levels of ANGPTL3, IL-1β, IL-6, Bax, P53, VEGF, and integrin αVβ3 were found to be upregulated after high-glucose stimulation or ANGPTL3 overexpression in HRMECs or diabetic retinal tissue. However, expression levels of the above markers were downregulated following fenofibrate intervention, blockage of integrin αVβ3 receptor, or ANGPTL3 siRNA interference. Conclusions We identified fenofibrate exerts its protective effects by inhibiting ANGPTL3-induced apoptosis and inflammation in diabetic retinopathy, which is a novel mechanism.