Oxidative Stress and Its Regulation in Diabetic Retinopathy

Abstract

Diabetic retinopathy is the retinal disease associated with hyperglycemia in patients who suffer from type 1 or type 2 diabetes. It includes maculopathy, involving the central retina and characterized by ischemia and/or edema, and peripheral retinopathy that progresses to a proliferative stage with neovascularization. Approximately 10% of the global population is estimated to suffer from diabetes, and around one in 5 of these individuals have diabetic retinopathy. One of the major effects of hyperglycemia is oxidative stress, the pathological state in which elevated production of reactive oxygen species damages tissues, cells, and macromolecules. The retina is relatively prone to oxidative stress due to its high metabolic activity. This review provides a summary of the role of oxidative stress in diabetic retinopathy, including a description of the retinal cell players and the molecular mechanisms. It discusses pathological processes, including the formation and effects of advanced glycation end-products, the impact of metabolic memory, and involvements of non-coding RNA. The opportunities for the therapeutic blockade of oxidative stress in diabetic retinopathy are also considered.

Oxidative Stress Mediates Epigenetic Modifications and the Expression of miRNAs and Genes Related to Apoptosis in Diabetic Retinopathy Patients

“…However, a higher ROS level is harmful for cells and tissues, and the subsequent mitochondrial dysfunction severely damages the lysosomes. Therefore, under pathological conditions these systems fail and generate large amounts of pro-oxidants [ 4 , 13 , 14 , 18 , 19 , 28 , 38 , 43 , 46 , 56 , 57 , 58 , 59 ]. Hyperglycemia leads over time to OS, which induces structural and functional damage to the retinal cell phenotypes, creating a harmful increased pro-oxidant and decreased antioxidant atmosphere [ 4 , 18 , 19 , 28 , 60 , 61 , 62 , 63 ].…”

“…Diabetic retinopathy (DR) is a microvascular–neurodegenerative complication of diabetes mellitus (DM) and the leading cause of visual loss in working-age people across many countries [ 1 , 2 ]. Sustained hyperglycemia, multi-metabolic pathway alteration, and a variety of endogenous/exogenous risk factors induce oxidative stress (OS) as well as preclinical changes in the retinal neurovascular unit (NVU) [ 3 , 4 , 5 ], as depicted in Figure 1 . A longer duration of DM, along with high blood pressure (HBP), augmented body mass index (BMI), and dyslipidemia, significantly increases the risk of developing DR [ 3 , 4 , 6 ].…”

“…Sustained hyperglycemia, multi-metabolic pathway alteration, and a variety of endogenous/exogenous risk factors induce oxidative stress (OS) as well as preclinical changes in the retinal neurovascular unit (NVU) [ 3 , 4 , 5 ], as depicted in Figure 1 . A longer duration of DM, along with high blood pressure (HBP), augmented body mass index (BMI), and dyslipidemia, significantly increases the risk of developing DR [ 3 , 4 , 6 ]. Outstanding strategies for DR management are emerging, including (1) innovative medical laser–surgical treatments, (2) chorio-retinal multimodal imaging, (3) electrophysiological probes of the retina and optic pathway, and (4) novel digital technology domains, including artificial intelligence (AI) and machine learning [ 3 , 6 , 7 , 8 , 9 , 10 , 11 ].…”

“…In this context, changes in miRNA expression levels have been reported to be associated with the development and progression of DR [ 28 ], and these molecular actors have also been introduced as useful disease biomarkers. Furthermore, a crosslink between the expression levels of miRNAs and OS pathways has been widely investigated [ 4 , 29 , 30 ].…”

Diabetic Retinopathy and Regulation of Mitochondrial Glutathione–Glutathione Peroxidase Axis in Hyperhomocysteinemia

“…Many metabolic, molecular, functional and structural abnormalities have been implicated in its development, but the exact molecular mechanism of this progressive disease remains unclear [ 1 , 2 ]. Oxidative stress, an imbalance between the formation and removal of free radicals, is considered to play a critical role in the development of diabetic retinopathy [ 3 , 4 , 5 ]. In diabetes, the retina experiences a double whammy, while the production of free radicals is increased, and the antioxidant defense system, including intracellular antioxidant glutathione (GSH) and the antioxidant defense enzymes superoxide dismutase and glutathione peroxidase (GPx), are downregulated [ 6 , 7 ].…”