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.
Highlights
The number of people with diabetes worldwide was 382 million in 2013 and nearly 592 million people are estimated to be diabetic by 2035 [1]
At primary stage patients should be encouraged to keep a close eye on their blood pressure, duration of the disease, hyperlipidemia, metabolic control, and hypertension
At the proliferative stages of the disease, the therapeutic interventions are effective in reducing visual loss; once diabetic retinopathy (DR) develops, additional mechanisms, including hypoxiainduced vascular endothelial growth factor (VEGF) production, contribute to retinal disease progression
Summary
The number of people with diabetes worldwide was 382 million in 2013 and nearly 592 million people are estimated to be diabetic by 2035 [1]. Molecular and biochemical mechanisms that have been implicated in diabetic retinopathy are increased flux of glucose through the polyol and hexosamine pathways, activation of protein kinase C, and increased advanced glycation end product formation [19] (Figures 1 and 2). The molecular mechanisms of VEGF overexpression induced by AGEs are not fully understood; recent investigations have shown that the AGE-RAGE interaction might increase VEGF gene transcription by NADPH oxidase-mediated ROS generation and the subsequent nuclear factor-κB (NF-κB) activation via Rasmitogen activated protein kinase (MAPK) pathway [43, 44] In another recent study it has been shown that knocking down of integrin-linked kinase (ILK) gene expression with siRNA inhibited the elevation of VEGF and intercellular adhesion molecule 1 (ICAM-1). An increased flux through hexosamine pathway is associated with TGF-β expression, PKC activation, and ECM production, all of which are linked with the pathogenesis of diabetic retinopathy [68]
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