Abstract
Diabetic retinopathy, a microvascular complication of diabetes, remains the leading cause of vision loss in working age adults. Hyperglycemia is considered as the main instigator for its development, around which other molecular pathways orchestrate. Of these multiple pathways, oxidative stress induces many metabolic, functional and structural changes in the retinal cells, leading to the development of pathological features characteristic of this blinding disease. An increase in cytosolic reactive oxygen species (ROS), produced by cytosolic NADPH oxidase 2 (Nox2), is an early event in the pathogenesis of diabetic retinopathy, which leads to mitochondrial damage and retinal capillary cell apoptosis. Activation of Nox2 is mediated through an obligatory small molecular weight GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), and subcellular localization of Rac1 and its activation are regulated by several regulators, rendering it a complex biological process. In diabetes, Rac1 is functionally activated in the retina and its vasculature, and, via Nox2-ROS, contributes to mitochondrial damage and the development of retinopathy. In addition, Rac1 is also transcriptionally activated, and epigenetic modifications play a major role in this transcriptional activation. This review focusses on the role of Rac1 and its regulation in the development and progression of diabetic retinopathy, and discusses some possible avenues for therapeutic interventions.
Highlights
Diabetes has become a major public health burden, and is considered to be an epidemic in the 21st century
Activation of polyol pathway, protein kinase C, increased oxidative stress and advanced glycation product formation are some of the pathways that are considered to play a role in the development diabetic retinopathy
The present review focuses on related C3 botulinum toxin substrate 1 (Rac1)-NADPH oxidase 2 (Nox2), and the role of other isoforms of NADPH oxidase (Nox) in diabetic retinopathy is beyond the scope of this review
Summary
Diabetes has become a major public health burden, and is considered to be an epidemic in the 21st century. Chronic hyperglycemia damages the retina, leading to progressive vision loss and blindness. It is the leading cause of blindness in working age adults around the world, and its incidence is expected to increase owing to the increasing global diabetes burden each year [5]. The incidence of retinopathy is reduced by 76%, and that of progression to advanced retinopathy, by 54%, if the intensive glycemic control is maintained [2].The United Kingdom Prospective Diabetes Study documented similar association between the severity of hyperglycemia and the incidence of diabetic retinopathy in type 2 diabetic patients [4]. Understanding the molecular mechanism of its development is essential for identifying potential future therapies for retinopathy in diabetes
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