Retinylamine Benefits Early Diabetic Retinopathy in Mice |
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Authors: | Haitao Liu Jie Tang Yunpeng Du Chieh Allen Lee Marcin Golczak Arivalagan Muthusamy David A Antonetti Alexander A Veenstra Jaume Amengual Johannes von Lintig Krzysztof Palczewski Timothy S Kern |
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Institution: | From the Departments of ‡Medicine and ;§Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, ;¶Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, and ;‖Veterans Affairs Medical Center, Cleveland, Ohio 44106 |
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Abstract: | 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. |
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Keywords: | diabetes endothelium inflammation reactive oxygen species (ROS) retina hyperglycemia retinal pigment epithelium retinylamine |
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