Nrf2 Activation Is a Potential Therapeutic Approach to Attenuate Diabetic Retinopathy
Nrf2 Activation Is a Potential Therapeutic Approach to Attenuate Diabetic Retinopathy
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DOI：
10.1167/iovs.17-22920
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发表时间：
2018-02-01
影响因子：
4.4
通讯作者：
Wilkinson-Berka, Jennifer L.
中科院分区：
文献类型：
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作者：
Deliyanti, Devy;Alrashdi, Saeed F.;Wilkinson-Berka, Jennifer L.
目的。氧化应激是糖尿病视网膜病变发生的一个原因；然而，通过增强抗氧化防御机制来治疗疾病的临床相关策略尚未得到充分探索。我们假设，使用新型Nrf2激活剂dh404增强核因子红细胞2相关因子2 （Nrf2）的抗氧化能力，可以保护糖尿病患者的视网膜，包括血视网膜屏障（BRB）的视力威胁破坏和大胶质Muller细胞的相关损伤。将Sprague-Dawley大鼠随机分为糖尿病大鼠和非糖尿病大鼠，灌胃dh404 10周。补充体外研究在培养Muller细胞暴露于高血糖。在糖尿病中，dh404可防止血管渗漏到视网膜和玻璃体腔，并可上调血管通透性和血管生成因子VEGF、血管生成素-2以及炎症介质tnf - α和IL-6。在糖尿病中，Muller细胞维持BRB的完整性，并随着胶质纤维酸性蛋白免疫标记的增加而变成胶质细胞，dh404对Muller细胞有保护作用。在糖尿病患者中，dh404通过增加血红素加氧酶-1、烟酰胺腺嘌呤二核苷酸/烟酰胺腺嘌呤二核苷酸磷酸（NADH/NADPH）奎宁氧化还原酶-1和Nrf2来增强视网膜的抗氧化能力。此外，通过双氢乙锭和8-氧-2'-脱氧鸟苷（8-OHdG）免疫标记以及NADPH氧化酶异构体表达测量，dh404减弱了糖尿病诱导的氧化应激增加。在Muller细胞中的研究支持了这些发现，dh404可以减轻高血糖诱导的血管通透性、血管生成和炎症介质以及氧化应激的增加。我们的数据表明dh404能够保护视网膜免受糖尿病引起的损伤，并可能预防视力丧失。
PURPOSE. Oxidative stress is a causal factor in the development of diabetic retinopathy; however, clinically relevant strategies to treat the disease by augmenting antioxidant defense mechanisms have not been fully explored. We hypothesized that boosting nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant capacity with the novel Nrf2 activator dh404, would protect the retina in diabetes including vision-threatening breakdown of the blood-retinal barrier (BRB) and associated damage to macroglial Muller cells.METHODS. Sprague-Dawley rats were randomized to become diabetic or nondiabetic and administered dh404 by gavage for 10 weeks. Complementary in vitro studies were performed in cultured Muller cells exposed to hyperglycemia.RESULTS. In diabetes, dh404 prevented vascular leakage into the retina and vitreous cavity as well as upregulation of the vascular permeability and angiogenic factors, VEGF, and angiopoietin-2, and inflammatory mediators, including TNF-alpha and IL-6. Muller cells, which maintain BRB integrity and become gliotic in diabetes with increased immunolabeling for glial fibrillary acidic protein, were protected by dh404. In diabetes, dh404 bolstered the antioxidant capacity of the retina with an increase in hemeoxygenase-1, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) quinine oxido-reductase-1, and Nrf2. Further, dh404 attenuated the diabetes-induced increase in oxidative stress as measured by dihydroethidium and 8-oxo-2'-deoxyguanosine (8-OHdG) immunolabeling as well as NADPH oxidase isoform expression. Studies in Muller cells supported these findings with dh404 attenuating the hyperglycemia-induced increase in vascular permeability, angiogenic and inflammatory mediators, and oxidative stress.CONCLUSIONS. Our data demonstrate the ability of dh404 to protect the retina against diabetes-induced damage and potentially prevent vision loss.