title: Increased Oxidative and Nitrative Stress Accelerates Aging of the Retinal Vasculature in the Diabetic Retina.
abstract: Hyperglycemia-induced retinal oxidative and nitrative stress can accelerate vascular cell aging, which may lead to vascular dysfunction as seen in diabetes. There is no information on whether this may contribute to the progression of diabetic retinopathy (DR). In this study, we have assessed the occurrence of senescence-associated markers in retinas of streptozotocin-induced diabetic rats at 8 and 12 weeks of hyperglycemia as compared to normoglycemic aging (12 and 14 months) and adult (4.5 months) rat retinas. We have found that in the diabetic retinas there was an up-regulation of senescence-associated markers SA-β-Gal, p16INK4a and miR34a, which correlated with decreased expression of SIRT1, a target of miR34a. Expression of senescence-associated factors primarily found in retinal microvasculature of diabetic rats exceeded levels measured in adult and aging rat retinas. In aging rats, retinal expression of senescence associated-factors was mainly localized at the level of the retinal pigmented epithelium and only minimally in the retinal microvasculature. The expression of oxidative/nitrative stress markers such as 4-hydroxynonenal and nitrotyrosine was more pronounced in the retinal vasculature of diabetic rats as compared to normoglycemic aging and adult rat retinas. Treatments of STZ-rats with the anti-nitrating drug FeTPPS (10mg/Kg/day) significantly reduced the appearance of senescence markers in the retinal microvasculature. Our results demonstrate that hyperglycemia accelerates retinal microvascular cell aging whereas physiological aging affects primarily cells of the retinal pigmented epithelium. In conclusion, hyperglycemia-induced retinal vessel dysfunction and DR progression involve vascular cell senescence due to increased oxidative/nitrative stress.
authors.affiliation: Dept. of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Folami
authors.initials: F
authors.lastname: Lamoke
authors.affiliation: Dept. of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Shaw
authors.affiliation: Dept. of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Jianghe
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Sudha
authors.initials: S
authors.lastname: Ananth
authors.affiliation: Dept. of Medicine, Section of Gastroenterology/Hepatology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Duncan
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Pamela
authors.initials: P
authors.lastname: Martin
authors.affiliation: Dept. of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartoli
mesh_terms: D000375:Aging; D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008055:Lipids / Q000737:chemistry; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D009584:Nitrogen / Q000737:chemistry*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology*; D056564:Sirtuin 1 / Q000378:metabolism; D013311:Streptozocin / Q000737:chemistry
chemical_list: D000447:Aldehydes; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008055:Lipids; D035683:MicroRNAs; D012333:RNA, Messenger; D013311:Streptozocin; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C027576:4-hydroxy-2-nonenal; D009584:Nitrogen