Retinylamine Benefits Early Diabetic Retinopathy in Mice
Retinylamine Benefits Early Diabetic Retinopathy in Mice
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DOI：
10.1074/jbc.m115.655555
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发表时间：
2015-08-28
影响因子：
4.8
通讯作者：
Kern, Timothy S.
中科院分区：
文献类型：
--
作者：
Liu, Haitao;Tang, Jie;Kern, Timothy S.
背景：糖尿病视网膜病变（DR）的发展尚不完全清楚。给药的视黄胺储存在视网膜色素上皮（RPE）中，在那里它影响眼视觉周期。结果：视黄胺可抑制早期DR的血管和神经病变。结论：RPE和视觉周期都是抑制DR的新靶点。意义：视觉相关过程可促进DR的发生。最新证据表明，视网膜外细胞在糖尿病视网膜病变（DR）的发病机制中起重要作用。在这里，我们研究了视觉周期抑制剂视黄胺（Ret-NH2）对早期DR病变发展的影响。野生型（WT） C57BL/6J小鼠（雄性，诱导糖尿病时2月龄）用链脲霉素诱导糖尿病，部分小鼠每周1次给予Ret-NH2。对卵磷脂-视黄醇酰基转移酶（LRAT）缺陷小鼠和P23H突变小鼠进行了类似的研究。小鼠在研究2 （WT和Lrat(-/-)）和8个月（WT）后安乐死，以评估血管组织病理学、白蛋白积累、视觉功能以及视网膜生化和生理异常。在体内处理的白细胞中检测Ret-NH2的非视网膜效应。2、8个月时，糖尿病小鼠视网膜超氧化物的产生和炎症蛋白的表达显著增加，8个月时，糖尿病小鼠视网膜变性毛细血管的数量和神经视网膜白蛋白的积累显著增加。每周1次给药Ret-NH2可抑制神经视网膜毛细血管变性和白蛋白积累，显著降低糖尿病诱导的视网膜超氧化物和炎症蛋白的表达。Lrat（-/-）糖尿病小鼠的超氧化物生成也受到抑制。与对照糖尿病小鼠的白细胞相比，经Ret-NH2处理的糖尿病小鼠的白细胞对视网膜内皮细胞的体外毒性明显降低。每周1次给药Ret-NH2可显著抑制糖尿病小鼠早期DR病变的发病机制。视觉周期是抑制DR的新靶点。
Background: The development of diabetic retinopathy (DR) is incompletely understood. Administered retinylamine is stored in the retinal pigmented epithelium (RPE) where it affects the ocular visual cycle. Results: Retinylamine inhibited vascular and neural lesions of early DR. Conclusion: Both the RPE and visual cycle are novel targets for the inhibition of DR. Significance: Vision-related processes can contribute to DR.Recent evidence suggests an important role for outer retinal cells in the pathogenesis of diabetic retinopathy (DR). Here we investigated the effect of the visual cycle inhibitor retinylamine (Ret-NH2) on the development of early DR lesions. Wild-type (WT) C57BL/6J mice (male, 2 months old when diabetes was induced) were made diabetic with streptozotocin, and some were given Ret-NH2 once per week. Lecithin-retinol acyltransferase (LRAT)-deficient mice and P23H mutant mice were similarly studied. Mice were euthanized after 2 (WT and Lrat(-/-)) and 8 months (WT) of study to assess vascular histopathology, accumulation of albumin, visual function, and biochemical and physiological abnormalities in the retina. Non-retinal effects of Ret-NH2 were examined in leukocytes treated in vivo. Superoxide generation and expression of inflammatory proteins were significantly increased in retinas of mice diabetic for 2 or 8 months, and the number of degenerate retinal capillaries and accumulation of albumin in neural retina were significantly increased in mice diabetic for 8 months compared with nondiabetic controls. Administration of Ret-NH2 once per week inhibited capillary degeneration and accumulation of albumin in the neural retina, significantly reducing diabetes-induced retinal superoxide and expression of inflammatory proteins. Superoxide generation also was suppressed in Lrat(-/-) diabetic mice. Leukocytes isolated from diabetic mice treated with Ret-NH2 caused significantly less cytotoxicity to retinal endothelial cells ex vivo than did leukocytes from control diabetics. Administration of Ret-NH2 once per week significantly inhibited the pathogenesis of lesions characteristic of early DR in diabetic mice. The visual cycle constitutes a novel target for inhibition of DR.