Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina
Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina
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DOI：
10.1073/pnas.1314575110
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发表时间：
2013-10-08
影响因子：
11.1
通讯作者：
Kern, Timothy S.
中科院分区：
文献类型：
--
作者：
Du, Yunpeng;Veenstra, Alexander;Kern, Timothy S.
越来越多的证据表明，感光细胞在糖尿病视网膜病变的早期发展中起着以前未被认识到的作用，但其发生的机制尚不清楚。已知抑制氧化应激可抑制早期糖尿病视网膜病变的血管病变，我们研究了糖尿病诱导的视网膜氧化应激是否来自光感受器。使用组织化学（二氯荧光素和二氢乙啶）和生物发光（光泽精）方法，在患糖尿病2个月（处死时为4个月龄）的雄性C57 BL/6 J小鼠视网膜中评估超氧化物生成。通过遗传（视蛋白（-/-））和化学（碘乙酸）技术在体内消除光感受器。免疫印迹法测定细胞间粘附分子1和诱导型一氧化氮合酶的表达。糖尿病小鼠视网膜超氧化物的生成在夜间比白天增加。光感受器是视网膜中活性氧的主要来源，它们的缺失（在视蛋白（-/-）小鼠中遗传或用碘乙酸急性）抑制了预期的糖尿病诱导的剩余视网膜中超氧化物和炎性蛋白的增加。线粒体和NADPH氧化酶都有助于观察到的视网膜超氧化物的产生，这可以在体内抑制与亚甲蓝或夹竹桃苷。光感受器是糖尿病小鼠视网膜产生超氧化物的主要来源。靶向光感受器氧化应激的药物可能为糖尿病视网膜病变提供独特的治疗方法。
Accumulating evidence suggests that photoreceptor cells play a previously unappreciated role in the development of early stages of diabetic retinopathy, but the mechanism by which this occurs is not clear. Inhibition of oxidative stress is known to inhibit the vascular lesions of early diabetic retinopathy, and we investigated whether the diabetes-induced oxidative stress in the retina emanates from photoreceptors. Superoxide generation was assessed in retinas of male C57BL/6J mice made diabetic for 2 mo (4 mo of age when killed) using histochemical (dichlorofluorescein and dihydroethidine) and bioluminescence (lucigenin) methods. Photoreceptors were eliminated in vivo by genetic (opsin(-/-)) and chemical (iodoacetic acid) techniques. Immunoblots were used to measure expression of intercellular adhesion molecule 1 and the inducible form of nitric oxide synthase. Diabetes increased the generation of superoxide by diabetic mouse retina more at night than during the day. Photoreceptors were the major source of reactive oxygen species in the retina, and their deletion (either genetically in opsin(-/-) mice or acutely with iodoacetic acid) inhibited the expected diabetes-induced increase in superoxide and inflammatory proteins in the remaining retina. Both mitochondria and NADPH oxidase contributed to the observed retinal superoxide generation, which could be inhibited in vivo with either methylene blue or apocynin. Photoreceptors are the major source of superoxide generated by retinas of diabetic mice. Pharmaceuticals targeting photoreceptor oxidative stress could offer a unique therapy for diabetic retinopathy.