Oxidative stress and epigenetic modifications in the pathogenesis of diabetic retinopathy

Abstract

Diabetic retinopathy remains the major cause of blindness among working age adults. Although a number of metabolic abnormalities have been associated with its development, due to complex nature of this multi-factorial disease, a link between any specific abnormality and diabetic retinopathy remains largely speculative. Diabetes increases oxidative stress in the retina and its capillary cells, and overwhelming evidence suggests a bidirectional relationship between oxidative stress and other major metabolic abnormalities implicated in the development of diabetic retinopathy. Due to increased production of cytosolic reactive oxygen species, mitochondrial membranes are damaged and their membrane potentials are impaired, and complex III of the electron transport system is compromised. Suboptimal enzymatic and nonenzymatic antioxidant defense system further aids in the accumulation of free radicals. As the duration of the disease progresses, mitochondrial DNA (mtDNA) is damaged and the DNA repair system is compromised, and due to impaired transcription of mtDNA-encoded proteins, the integrity of the electron transport system is encumbered. Due to decreased mtDNA biogenesis and impaired transcription, superoxide accumulation is further increased, and the vicious cycle of free radicals continues to self-propagate. Diabetic milieu also alters enzymes responsible for DNA and histone modifications, and various genes important for mitochondrial homeostasis, including mitochondrial biosynthesis, damage and antioxidant defense, undergo epigenetic modifications. Although antioxidant administration in animal models has yielded encouraging results in preventing diabetic retinopathy, controlled longitudinal human studies remain to be conducted. Furthermore, the role of epigenetic in mitochondrial homeostasis suggests that regulation of such modifications also has potential to inhibit/retard the development of diabetic retinopathy.

Diabetic retinopathy: current understanding, mechanisms, and treatment strategies

“…Finally, expanding the scope of pathogenic processes that are therapeutically targeted beyond vascular leakage and neovascularization to include neuroprotection and intraretinal revascularization would be highly desirable endpoints in DR. The concept of epigenetic modifications associated with the metabolic memory phenomenon is an additional pathogenic process worthy of therapeutic attention (123). Identification and targeting of key epigenetic mechanisms could help to slow down the progression of DR in patients, especially those with a prior history of poor glycemic control.…”

Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

“…The pathogenesis of diabetic microvascular histopathology involves retinal oxidative stress. 1,2 Recent evidence points to dysfunctional rod photoreceptor cells as a primary source of this oxidative stress. 1,[3][4][5][6] Although the nature of the rod dysfunction is not entirely understood, it likely involves dysregulation of photoreceptor ion channels.…”

“…The present study had three goals: (1) to confirm the correction of photoreceptor dysfunction using alternative (i.e., non-MEMRI) methods with 11-cis-retinaldehyde in diabetic mice; (2) to test for beneficial effects of 11-cis-retinaldehyde or 9-cis-retinaldehyde (a chromophore surrogate) on impaired cone-based visual performance of diabetic mice as measured by photopic optokinetic tracking (OKT) ( [36][37][38][39][40] ; and (3) to test the hypothesis that exogenous retinaldehydes correct retinal oxidative stress in diabetic mice.…”

Oxidative Stress Biomarkers for Diabetic Retinopathy and Medical Management Affecting Oxidative Stress

“…DR is one of the major microvascular complications affecting the vision and is the leading cause of blindness in working-age adults [3]. It progresses from mild nonproliferative abnormalities, characterized by increased vascular permeability, to nonproliferative diabetic retinopathy (NPDR), characterized by vascular closure, to proliferative diabetic retinopathy (PDR), characterized by the growth of new blood vessels in the retina and the posterior surface of the vitreous [4] (Figure 1).…”