Deng Guotao, Moran Elizabeth P, Cheng Rui, Matlock Greg, Zhou Kelu, Moran David, Chen Danyang, Yu Qiang, Ma Jian-Xing
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
Invest Ophthalmol Vis Sci. 2017 Oct 1;58(12):5030-5042. doi: 10.1167/iovs.16-21402.
Clinical studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate has therapeutic effects on diabetic retinopathy (DR). The purpose of this study was to identify a novel PPARα agonist and to evaluate its beneficial effects on DR.
The transcriptional activity of PPARα was measured by a luciferase-based promoter assay. TUNEL was used to evaluate apoptosis in retinal precursor cells (R28). Diabetes was induced in rats by injection of streptozotocin. Retinal inflammation was examined using leukostasis assay, and retinal vascular leakage was measured using permeability assay. Retinal function was measured using electroretinogram (ERG) recording, and retinal apoptosis was quantified using the cell death ELISA. The anti-angiogenic effect was evaluated in the oxygen-induced retinopathy (OIR) model.
A compound, 7-chloro-8-methyl-2-phenylquinoline-4-carboxylic acid (Y-0452), with a chemical structure distinct from existing PPARα agonists, activated PPARα transcriptional activity and upregulated PPARα expression. Y-0452 significantly inhibited human retinal capillary endothelial cell migration and tube formation. The compound also protected R28 cells against apoptosis and inhibited NF-κB signaling in R28 cells exposed to palmitate. In diabetic rats, Y-0452 ameliorated leukostasis and vascular leakage in the retina. In addition, Y-0452 preserved the retinal function and reduced retinal cell death in diabetic rats. Y-0452 also alleviated retinal neovascularization in the OIR model.
Y-0452 is a novel PPARα agonist and has therapeutic potential for DR.
临床研究表明，过氧化物酶体增殖物激活受体α（PPARα）激动剂非诺贝特对糖尿病视网膜病变（DR）具有治疗作用。本研究的目的是鉴定一种新型PPARα激动剂，并评估其对DR的有益作用。
通过基于荧光素酶的启动子分析来测量PPARα的转录活性。采用TUNEL法评估视网膜前体细胞（R28）中的细胞凋亡。通过注射链脲佐菌素诱导大鼠患糖尿病。使用白细胞淤滞试验检查视网膜炎症，并使用通透性试验测量视网膜血管渗漏。使用视网膜电图（ERG）记录来测量视网膜功能，并使用细胞死亡ELISA对视网膜细胞凋亡进行定量。在氧诱导性视网膜病变（OIR）模型中评估抗血管生成作用。
一种化合物，7-氯-8-甲基-2-苯基喹啉-4-羧酸（Y-0452），其化学结构与现有的PPARα激动剂不同，可激活PPARα转录活性并上调PPARα表达。Y-0452显著抑制人视网膜毛细血管内皮细胞迁移和管腔形成。该化合物还可保护R28细胞免受凋亡，并抑制暴露于棕榈酸的R28细胞中的NF-κB信号传导。在糖尿病大鼠中，Y-0452改善了视网膜中的白细胞淤滞和血管渗漏。此外，Y-0452保留了糖尿病大鼠的视网膜功能并减少了视网膜细胞死亡。Y-0452还减轻了OIR模型中的视网膜新生血管形成。
Y-0452是一种新型PPARα激动剂，对DR具有治疗潜力。
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