Targeting epigenetic modifications as a potential therapeutic option for diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is the leading cause of visual impairment in adults of working age (20-65 years) in developed countries. The metabolic memory phenomena (persistent effect of a glycemic insult even after retrieved) associated with it has increased the risk of developing the complication even after the termination of the glycemic insult. Hence, the need for finding early diagnosis and treatment options has been of great concern. Epigenetic modifications which generally occur during the beginning stages of the disease are responsible for the metabolic memory effect. Therefore, the therapy based on the reversal of the associated epigenetic mechanism can bring new insight in the area of early diagnosis and treatment mechanism. This review discusses the diabetic retinopathy, its pathogenesis, current treatment options, need of finding novel treatment options, and different epigenetic alterations associated with DR. However, the main focus is emphasized on various epigenetic modifications particularly DNA methylation which are responsible for the initiation and progression of diabetic retinopathy and the use of different epigenetic inhibitors as a novel therapeutic option for DR. K E Y W O R D Sdiabetic retinopathy, DNA methylation, epigenetic modification, metabolic memory

LncRNA GAS5 suppresses ER stress‑induced apoptosis and inflammation by regulating SERCA2b in HG‑treated retinal epithelial cell

“…Diabetes is a serious and complex disease characterized by chronic hyperglycemia, which aggravates a series of metabolic reactions and increases the production of advanced glycosylation end products (aGes). it has been reported that in diabetes the development of AGE-induced retinal inflammation results in blood-retinal barrier damage, which in turn leads to diabetic macular edema and retinal neovascularization (1,2). Although blood glucose control has been reported to significantly reduce the incidence of microvascular complications, some patients still suffer from proliferative diabetic retinopathy (dr) for >30 years (3).…”

Integrative Computational Approach Revealed Crucial Genes Associated With Different Stages of Diabetic Retinopathy

“…The level of MMP-9 differs with the stages of DR and was found to contribute more than MMP-1 in DR pathogenesis (Kwon et al, 2016). Various histone modifications, DNA methylations, and their role in metabolic memory formation (Mishra and Kowluru, 2016;Kumari et al, 2020) are reported for MMP9 during hyperglycemic conditions. SPARC (Secreted Protein Acidic And Cysteine Rich), a gene that encodes cysteine-rich acidic matrix-associated protein, is also involved in the development of DR. Retinal basement membrane of Type2DM patients showing thickening and permeability changes is found to secrete the protein encoded by SPARC (Watanabe et al, 2009).…”

“…Various epigenetic modifications such as DNA methylation, histone modifications, microRNA (miRNA), etc., occurring during the early stage of diabetes do not only regulate the expression of various genes but are also responsible for the metabolic memory phenomena (deleterious effect induced by prior glycemic exposure regardless of later glycemic control) associated with diabetes (Mishra and Kowluru, 2016;Kumari et al, 2020). This triggers the need for developing early diagnosis and treatment methods.…”

Involvement of miR‐126 rs4636297 and miR‐146a rs2910164 polymorphisms in the susceptibility for diabetic retinopathy: a case–control study in a type 1 diabetes population

“…Epigenetic modifications regulate the complex interplay between genes and environmental factors without altering the DNA sequence (Kowluru & Mishra 2015; Kumari et al 2019). The three major classes of epigenetic factors are DNA methylation, histone modification and non‐coding RNAs (ncRNAs) (Kowluru & Mishra 2015; Kumari et al 2019). NcRNAs are regulatory RNAs that lack protein‐coding capacity.…”

“…So far, the most widely studied class of ncRNAs are miRNAs, which are small ncRNAs of ~22 nt that regulate expression of more than 60% of protein‐coding genes, consequently controlling various biological and pathological processes, such as cellular growth, apoptosis, differentiation, metabolism and immune response (Esteller 2011; Assmann et al 2017b; Martinez & Peplow 2019; Satari et al 2019). Growing evidence suggests the involvement of several miRNAs in DR pathogenesis (Joglekar et al 2016; Gong & Su 2017; Kumari et al 2019; Martinez & Peplow 2019; Satari et al 2019). MiRNA‐126 expression seems to be downregulated in serum of diabetic patients with DR (Rezk et al 2016; Barutta et al 2017; Qin et al 2017; Martinez & Peplow 2019), endothelial cells (ECs) and retinal pericytes of a murine DR model (Fang et al 2017), and in retina of streptozotocin (STZ)‐induced diabetic rats (Ye et al 2014).…”