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.

Update on the Effects of Antioxidants on Diabetic Retinopathy: In Vitro Experiments, Animal Studies and Clinical Trials

“…The phenomenon, described as metabolic memory, is related to the deleterious effects on tissues caused by hyperglycaemia, even though there are strict glycemic controls. Thus, pathways related to regulatory role of microRNAs, histone modifications, DNA methylation and the sirtuins-histones function can act as epigenetic modifiers and modulators [ 4 , 13 , 14 ].…”

Remodeling of Retinal Architecture in Diabetic Retinopathy: Disruption of Ocular Physiology and Visual Functions by Inflammatory Gene Products and Pyroptosis

“…Equally, inflammatory genes in retinal cells that are regulated by epigenetics have also been demonstrated. Histone modifications by enzymes such as histone methyltransferases, histone demethylases, histone acetyltransferases, and histone deacetylases can reversibly change gene expression patterns ( Pradhan et al, 2016 ; Zhang et al, 2017 ). Therefore, elucidating epigenetic regulation could certainly lead to the discovery and development of novel therapeutic agents for DR. Popularly known as ‘epi-drugs,’ such as histone demethylases, HATs, DNA methylation inhibitors, and HDACs are presently being analyzed for other medical conditions like cancer ( Shi, 2007 ).…”

“…Hyperglycemia’s harmful effects are directly related to the structural damage inflicted on small retinal blood vessels and are governed by the systemic and local ocular factors. Although there are genetic factors also at play, but individuals with elevated blood glucose levels have severe retinopathy than those with strict blood glucose control ( Kuo et al, 2014 ; Pradhan et al, 2016 ). HbA1c measures overall glucose level in blood over a period of 3 months.…”

A Disease-Associated MicroRNA Cluster Links Inflammatory Pathways and an Altered Composition of Leukocyte Subsets to Noninfectious Uveitis

“…[8][9][10][11][12] Despite our growing understanding that susceptibility to NIU is in part genetic, and epigenetic modulation contributes to various ocular conditions, studies investigating the epigenetic landscape of uveitis are scarce. [13][14][15] One of the mechanisms through which epigenetic regulation of gene expression takes place is through microRNAs (miRNAs). 16 miRNAs are small RNAs abundantly found in almost all biological tissues.…”