Search

Diabetic retinopathy is a major vision threatening disease among working age adults, and increased oxidative stress is one of the prime causative factors in its pathogenesis. Increased reactive oxygen species (ROS) in the cytosol damage mitochondria, and due to compromised antioxidant signaling system and dysfunctional mitochondria with damaged mitochondrial DNA, ROS continue to pile up, accelerating capillary cell loss. In addition to other cellular and enzymatic defense systems, the retina is also equipped with the nuclear erythroid-2-p45-related factor-2 (Nrf2) antioxidant response element signaling pathway, which controls the expression of genes important in detoxification and elimination of ROS. However, in diabetes, its transcriptional activity is impaired, further exacerbating and exposing the retina to elevated stress. Diabetic milieu also alters epigenetic factors responsible for chromatin modifications and gene regulation, and kelch-like ECH-associated protein 1 (Keap1), important in regulating Nrf2-antioxidant signaling axis, is epigenetically modified, impeding nuclear translocation of Nrf2, and this inhibits the transcription of genes with Antioxidant Response Element. This review discusses antioxidant signaling, especially the role of Nrf2, in diabetic retinopathy, and possible involvement of epigenetic modifications in antioxidant signaling and Nrf2 transcriptional activity. Therapies targeting Nrf2 activation, including epigenetic modifications, have potentional to prevent mitochondrial damage and inhibit the development, and progression of this sight-threatening disease which most of the patients get after 20–25 years of diabetes. [ABSTRACT FROM AUTHOR]

Aim In the pathogenesis of diabetic retinopathy, reactive oxygen species (ROS) are elevated in the retina and the mitochondria are damaged, resulting in accelerated apoptosis. Dyslipidemia is also considered as one of the major factors in its development, and our aim is to investigate the compounding effect of hyperlipidemia in retinopathy. Methods Retinal ROS, mitochondrial damage and vascular pathology were investigated in Zucker diabetic fatty rats (ZDF, type 2 diabetes model), during the age that spans from hyperlipidemia/pre-hyperglycemia (6 weeks), to severe hyperglycemia/moderate hyperlipidemia (~ 12 weeks), and ultimately to severe hyperglycemia/hyperlipidemia (20–40 weeks). For comparison, retina from streptozotocin-induced Wistar rats (type 1 diabetic for 10–40 weeks) was analyzed. Results Compared to age-matched lean rats, despite increased retinal cytosolic ROS in 6-week-old ZDF rats, mitochondrial dysfunction and DNA damage were not detected, and in 12-week-old ZDF rats, retinal mitochondria were dysfunctional, but mtDNA damage and vascular pathology (cell apoptosis and degenerative capillaries) were not detectable. Retina from 20-week-old ZDF rats (hyperglycemic for 14 weeks or less) had significant mitochondrial dysfunction, mtDNA damage and vascular pathology, and similar abnormalities were observed in 40-week-old ZDF rats. Although retinal mitochondrial dysfunction was observed in Wistar rats diabetic for 20 weeks, mtDNA damage and vascular pathology were not detectable till the duration of diabetes was further extended. Conclusions Hyperlipidemia, in a hyperglycemic milieu, potentiates mitochondrial damage and augments the development of retinopathy. Control of dyslipidemia in pre-diabetic patients may prevent/delay the development and the progression of this devastating disease. [ABSTRACT FROM AUTHOR]

Increase in matrix metalloproteinase-9 (MMP-9) is implicated in retinal capillary cell apoptosis, a phenomenon which precedes the development of diabetic retinopathy. MMP-9 promoter has multiple sites for binding the transcriptional factors, including two for activator protein 1 (AP-1). The binding of AP-1, a heterodimer of c-Jun and c-Fos, is regulated by posttranslational modifications, and in diabetes, deacetylating enzyme, Sirt1, is inhibited. Our aim, is to investigate the molecular mechanism of MMP-9 transcriptional regulation in diabetes. Binding of AP-1 (c-Jun, c-Fos) at the MMP-9 promoter, and AP-1 acetylation were analyzed in retinal endothelial cells incubated in normal or high glucose by chromatin-immunoprecipitation and co-immunoprecipitation respectively. Role of AP-1 in MMP-9 regulation was confirmed by c-Jun or c-Fos siRNAs, and that of its acetylation, by Sirt1 overexpression. In vitro results were validated in the retina from diabetic mice overexpressing Sirt1, and in the retinal microvessels from human donors with diabetic retinopathy. In experimental models, AP-1 binding was increased at the proximal and distal sites of the MMP-9 promoter, and similar phenomenon was confirmed in the retinal microvessels from human donors with diabetic retinopathy. Silencing of AP-1, or overexpression of Sirt1 ameliorated glucose-induced increase in MMP-9 expression and cell apoptosis. Thus, in diabetes, due to Sirt1 inhibition, AP-1 is hyperacetylated, which increases its binding at MMP-9 promoter, and hence, activation of Sirt1 could inhibit the development of diabetic retinopathy by impeding MMP-9-mediated mitochondrial damage. J. Cell. Physiol. 231: 1709-1718, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In diabetic retinopathy, increased cytosolic reactive oxygen species, produced by NADPH oxidase (Nox), damage mitochondria, and this accelerates apoptosis of retinal capillary cells, resulting in the histopathology. Activation of Nox2 is mediated by a small molecular weight GTPase, Rac1, and retinal Rac1 is activated in diabetes. Our goal is to investigate the molecular mechanism responsible for transcriptional activation of Rac1 in the development of diabetic retinopathy. Using retinal microvessels, the site of histopathology associated with diabetic retinopathy, from streptozotocin-induced diabetic rats, we investigated the binding of the nuclear transcriptional factor- k B (NF- k B) at Rac1 promoter. Since activation of NF- k B is regulated by its acetylation-deacetylation, the role of acetylation in Rac1 transcription was confirmed in the retina from diabetic mice overexpressing a deacetylase, Sirtuin 1. Diabetes increased the binding of p65 subunit of NF- k B at the Rac1 promoter. Overexpression of Sirtuin 1 prevented hyper-acetylation of p65, decreased its binding at the Rac1 promoter and ameliorated Rac1-Nox2 mediated mitochondrial damage. Thus, in diabetes Rac1 transcriptional activation in the retina is mediated by acetylation of NF- k B, and modulation of acetylation during the early stages of diabetic retinopathy has potential to inhibit/retard its development. [ABSTRACT FROM AUTHOR]