title: Retinylamine Benefits Early Diabetic Retinopathy in Mice.
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.
authors.affiliation: From the Departments of Medicine and.
authors.forename: Haitao
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Departments of Medicine and.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: From the Departments of Medicine and.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Du
authors.affiliation: From the Departments of Medicine and.
authors.forename: Chieh Allen
authors.initials: CA
authors.lastname: Lee
authors.affiliation: Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, and.
authors.forename: Arivalagan
authors.initials: A
authors.lastname: Muthusamy
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Antonetti
authors.affiliation: From the Departments of Medicine and.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Veenstra
authors.affiliation: Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Jaume
authors.initials: J
authors.lastname: Amengual
authors.affiliation: Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
authors.affiliation: Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.affiliation: From the Departments of Medicine and Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, Veterans Affairs Medical Center, Cleveland, Ohio 44106 tsk@case.edu.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
mesh_terms: D000217:Acyltransferases / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D002469:Cell Separation; D003930:Diabetic Retinopathy / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004224:Diterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010539:Permeability; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013481:Superoxides / Q000378:metabolism
chemical_list: D004224:Diterpenes; D013481:Superoxides; C009167:retinylamine; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase; D005947:Glucose
keywords: diabetes; endothelium; hyperglycemia; inflammation; reactive oxygen species (ROS); retina; retinal pigment epithelium; retinylamine