Increased Oxidative and Nitrative Stress Accelerates Aging of the Retinal Vasculature in the Diabetic Retina.

Folami Lamoke,Manuela Bartoli,Sudha Ananth,Pamela Martin,Sean Shaw,Michael Duncan,Jianghe Yuan,Alexander V Ljubimov

doi:10.1371/journal.pone.0139664

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.

Highlights

Hyperglycemia-induced dysfunction of retinal blood vessels is a major contributing factor in the pathogenesis of diabetic retinopathy (DR), the leading cause of blindness in working-age adults [1,2,3]
In this study we have investigated the effects of hyperglycemia in promoting retinal vascular cell premature aging, a molecular event shown to lead to vascular dysfunction and induction of inflammatory processes, all factors involved in the pathogenesis of DR [10, 20]
Cellular senescence can be divided into two categories: replicative senescence, which is dependent on the number of spontaneously completed cell divisions, and stress-induced premature senescence (SIPS) [23, 46]

Summary

Introduction

Hyperglycemia-induced dysfunction of retinal blood vessels is a major contributing factor in the pathogenesis of diabetic retinopathy (DR), the leading cause of blindness in working-age adults [1,2,3]. Augmented oxidative and nitrative stress, due to increased production of reactive oxygen and nitrogen species (ROS and RNS, respectively) [10, 11] and impaired endogenous antioxidant ability [12], have been shown to induce inflammatory responses leading to capillary cell dysfunction and death [10]. Oxidative stress-induced vascular inflammation occurs during physiological aging [13,14,15,16] where vascular senescence plays a key role in the pathogenesis of age-associated cardiovascular disease [17,18,19,20,21]. Endothelial cells (ECs) and surrounding tissues undergo structural alterations in a complex senescence process characteristically similar to what occurs during physiological aging [25,26,27,28,29], but not including replicative senescenceassociated telomere shortening and its downstream consequences [30]

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Conclusion