Genetic and epigenetic modifications in the pathogenesis of diabetic retinopathy: a molecular link to regulate gene expression

Abstract

Intensification in the frequency of diabetes and the associated vascular complications has been a root cause of blindness and visual impairment worldwide. One such vascular complication which has been the prominent cause of blindness; retinal vasculature, neuronal and glial abnormalities is diabetic retinopathy (DR), a chronic complicated outcome of Type 1 and Type 2 diabetes. It has also become clear that "genetic" variations in population alone can't explain the development and progression of diabetes and its complications including DR. DR experiences engagement of foremost mediators of diabetes such as hyperglycemia, oxidant stress, and inflammatory factors that lead to the dysregulation of "epigenetic" mechanisms involving histone acetylation and histone and DNA methylation, chromatin remodeling and expression of a complex set of stress-regulated and disease-associated genes. In addition, both elevated glucose concentration and insulin resistance leave a robust effect on epigenetic reprogramming of the endothelial cells too, since endothelium associated with the eye aids in maintaining the vascular homeostasis. Furthermore, several studies conducted on the disease suggest that the modifications of the epigenome might be the fundamental mechanism(s) for the proposed metabolic memory' resulting into prolonged gene expression for inflammation and cellular dysfunction even after attaining the glycemic control in diabetics. Henceforth, the present review focuses on the aspects of genetic and epigenetic alterations in genes such as vascular endothelial growth factor and aldose reductase considered being associated with DR. In addition, we discuss briefly the role of the thioredoxin-interacting protein TXNIP, which is strongly induced by high glucose and diabetes, in cellular oxidative stress and mitochondrial dysfunction potentially leading to chromatin remodeling and ocular complications of diabetes. The identification of disease-associated genes and their epigenetic regulations will lead to potential new drugs and gene therapies as well as personalized medicine to prevent or slow down the progression of DR.

Keywords: diabetic retinopathy; epigenetics; genetics; mitochondrial dysfunction; vascular complications.

Figure 1

Hyperglycemia and potential metabolic pathways involved in the pathogenesis of diabetic complications including retinopathy. TXNIP is highly induced by diabetes and high glucose in most cell types examined thus far, and enhanced glucose metabolites such as glucose-6-phosphate, fructose-6-phosphate and glucosamine-6-phosphate as well as RAGE activation are known to activate TXNIP gene expression. TXNIP has been defined as a pro-oxidative stress, pro-inflammatory and pro-apoptotic protein involved in diabetes and its complications [20,21].

Figure 2

Hyperglycemia-induced TXNIP upregulation, inhibition of Trx1/Trx2 and mitochondrial stress may alter epigenome regulation by changing histone and DNA epigenetic substrates in DR [24]. Some histone H3 and promoter DNA modification examples are shown. In general, histone acetylation and phosphorylation are activation marks while lysine methylations are repressive marks, although H3K4Me is an activation modification. Cytosine methylation at the CpG islands in proximal promoters is a repressive DNA transcriptional mark. Environmental factors such as diet, exercise, and sedentary lifestyle can influence epigenetics and gene expression in aging-related disorders including diabetes and neurodegenerative diseases.