Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications

Abstract

Oxidative stress, a cytopathic outcome of excessive generation of ROS and the repression of antioxidant defense system for ROS elimination, is involved in the pathogenesis of multiple diseases, including diabetes and its complications. Retinopathy, a microvascular complication of diabetes, is the primary cause of acquired blindness in diabetic patients. Oxidative stress has been verified as one critical contributor to the pathogenesis of diabetic retinopathy. Oxidative stress can both contribute to and result from the metabolic abnormalities induced by hyperglycemia, mainly including the increased flux of the polyol pathway and hexosamine pathway, the hyper-activation of protein kinase C (PKC) isoforms, and the accumulation of advanced glycation end products (AGEs). Moreover, the repression of the antioxidant defense system by hyperglycemia-mediated epigenetic modification also leads to the imbalance between the scavenging and production of ROS. Excessive accumulation of ROS induces mitochondrial damage, cellular apoptosis, inflammation, lipid peroxidation, and structural and functional alterations in retina. Therefore, it is important to understand and elucidate the oxidative stress-related mechanisms underlying the progress of diabetic retinopathy. In addition, the abnormalities correlated with oxidative stress provide multiple potential therapeutic targets to develop safe and effective treatments for diabetic retinopathy. Here, we also summarized the main antioxidant therapeutic strategies to control this disease.

Keywords: Antioxidant therapeutics; Diabetic retinopathy; Dysmetabolism; Epigenetic modification; Oxidative stress; Reactive oxygen species.

Graphical abstract

Fig. 1

The electron transportation chain and the generation of ROS in mitochondria. Complex I and II receive the electrons from NADH and FADH₂, respectively. Then the electrons are transported to coenzyme Q (CoQ), and then transferred to cytochrome C (Cyt C) in the complex III. Finally, complex IV offers the electrons to O₂ to produce H₂O. In this process, all the complexes pump protons out of mitochondrial matrix to form a gradient of protons between intermembrane space and mitochondrial matrix. The energy of the proton gradient drives ATP synthase to generate ATP. Hyperglycemia can induce the blockage of the normal electron transportation, and O₂ can accept the electrons to transform into reactive oxygen species.

Fig. 2

The Nox system is an enzymatic source of oxidative stress. It can utilize NADPH as substrates to transport the electron to molecular oxygen, and drive molecular oxygen to convert into reactive oxygen species.

Fig. 3

The metabolic abnormalities induced by hyperglycemia. The major pathways include the polyol pathway, the hexosamine biosynthesis pathway, the formation of advanced glycation end products (AGEs), and protein kinase C (PKC) activation, which contribute to ROS generation and aggravate oxidative stress to promote the pathogenies of retinopathy.

Fig. 4

Schematic diagram of epigenetic modifications in DR: diabetes induces oxidative stress, which leads to the altered expression of genes involved in histone (LSD1, KDM5A, HDACs), and DNA (DNMTs) modifications. Histone methylation (H3K4me1, H3K4me3H3K9me2, H3K4me2, H4K20me3) and acetylation (H3K9-Ac, p65 of NF-κB) modulate the binding of transcription factor (Nrf2, Sp1, NF-kB-p65) and alter the transcriptional levels of Gclc, Keap1, MMP-9, SOD2, and TXNIP. DNA methylation at POLG1 and MLH1 promoter represses their transcriptional levels in DR. MicroRNAs (miR-200b, miR-195, miR-211 …) and lncRNA (ANRIL, MIAT, MEG3, Sox2OT, NEAT1 …) regulate their target genes related to the development of DR. Although this scheme shows various epigenetic regulation, we cannot exclude the roles of many, yet identified, other histone and DNA modifications and miRNAs and lncRNA in DR.