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.

Figure 1

The four major mechanisms involved in DR are increased polyol pathway flux, increased AGE formation, activation of PKC, and polyol pathways.

Figure 2

Hyperglycemia-induced biochemical alterations precipitated by mitochondria-driven oxidative stress leading to diabetic complications including apoptosis, inflammation, and ultimately diabetic retinopathy.

Figure 3

Aldose reductase and the polyol pathway. Aldose reductase reduces aldehydes generated by reactive oxygen species (ROS) to inactive alcohols, and glucose to sorbitol, using NADPH as a cofactor. Glutathione (GSH), glutathione disulfide (GSSG), and sorbitol dehydrogenase (SDH).

Figure 4

(a) The established preventive measures including general, primary, and secondary preventive strategies. (b) Novel and emerging therapeutic targets including PKC inhibitors, VEGF inhibitors, ACE inhibitors, and drugs as antioxidants.