Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

Abstract

The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors.

Mediterranean Diet, Retinopathy, Nephropathy, and Microvascular Diabetes Complications: A Post Hoc Analysis of a Randomized Trial

“…Most of these components have been related to decreases in the risk of diabetic retinopathy (5,7,11-13,16). The MedDiet pattern promoted in both MedDiet interventions included several other dietary components reported to be beneficial in alleviating inflammation and oxidative stress and in decreasing insulin resistance and secretion, which are pathogenic factors in diabetes (30) and diabetic microvascular complications (31). In conjunction with the improvement in the aforementioned cardiometabolic risk factors, this adds biological plausibility to the present results.…”

Molecular and Biochemical Pathways of Catalpol in Alleviating Diabetes Mellitus and Its Complications

“…Pericytes participate in maintaining angiogenesis and regulating blood flow [ 128 ]. Excess glucose level increases sorbitol level through activation of polyol pathway, and an excess amount of sorbitol is accumulated among the cells, which causes osmotic stress and damage [ 129 ]. Hyperglycemia causes the accumulation of AGE and activates AGE–RAGE pathway.…”

“…Hyperglycemia causes the accumulation of AGE and activates AGE–RAGE pathway. Through this pathway, ROS is generated that exerts oxidative stress and recruits inflammatory cytokines such as TNFα, IL-1, IL-6, and IL-8 with an accumulation of adhesion molecules such as VCAM-1 and ICAM-1 by activating NF-κB [ 129 ]. Retinal neurodegeneration took place in retinal ganglion cells (RGCs) responsible for forming vision in the retina.…”

Selection Strategy of In Vivo Models for Ophthalmic Drug Development in Diabetic Retinopathy

“…Increase in glucose metabolism pathways, augmented production of AGE and activation of the PKC pathway are generally considered as the major mechanisms contributing to DR. These pathways result ultimately in oxidative stress, inflammation, vascular occlusion, neurodegeneration and subsequent upregulation of growth factors and cytokines [4,[268][269][270][271]. Despite many years of research it remains largely unknown which molecular and cellular pathways are the major drivers of DR pathogenesis and progression.…”