Abstract
Hyperglycaemia-induced oxidative stress appears to be involved in the aetiology of diabetic retinopathy (DR), a major public health issue, via altering DNA methylation process. We investigated the effect of hyperglycaemia on retinal DNA methyltransferase (DNMT) expression in diabetic mice, using Gene Expression Omnibus datasets. We also evaluated the effect of curcumin both on high glucose-induced reactive oxygen species (ROS) production and altered DNMT functions, in a cellular model of DR. We observed that three months of hyperglycaemia, in insulin-deficient Ins2Akita mice, decrease DNMT1 and DNMT3a expression levels. In retinal pigment epithelium (RPE) cells, we also demonstrated that high glucose-induced ROS production precedes upregulation of DNMT expression and activity, suggesting that changes in DNMT function could be mediated by oxidative stress via a potential dual effect. The early effect results in decreased DNMT activity, accompanied by the highest ROS production, while long-term oxidative stress increases DNMT activity and DNMT1 expression. Interestingly, treatment with 25 μM curcumin for 6 hours restores ROS production, as well as DNMT functions, altered by the exposure of RPE to acute and chronic high glucose concentration. Our study suggests that curcumin may represent an effective antioxidant compound against DR, via restoring oxidative stress and DNMT functions, though further studies are recommended.
Highlights
The growing incidence of diabetes and longer life span in the aging population point towards an increase in patients with diabetic retinopathy (DR), a diabetes-related microvascular complication which represents a major public health issue as one of the leading causes of blindness in elderly adults [1]
The present study investigated the effect of hyperglycaemia and high glucose-induced oxidative stress on retinal DNA methyltransferase (DNMT) activity and expression, as well as on LINE-1 methylation levels
Data analysis revealed that insulin-deficient Ins2Akita mice, but not STZ-induced diabetic mice, showed lower DNMT1 (MD = −0.28, p < 0 001) and DNMT3a (MD = −0.31, p < 0 001) expression levels compared to nondiabetic controls (Figures 1(b) and 1c)
Summary
The growing incidence of diabetes and longer life span in the aging population point towards an increase in patients with diabetic retinopathy (DR), a diabetes-related microvascular complication which represents a major public health issue as one of the leading causes of blindness in elderly adults [1]. Regardless of the type of diabetes, both hyperglycaemia and hyperglycaemia-induced oxidative stress have been identified as the major contributing factors [4, 5]. Oxidative stress has been shown to alter histone modifications and DNA methylation [7], which have been further recognized as potential epigenetic mechanisms involved in the pathophysiology of DR [8,9,10,11]. Methylation almost exclusively occurs at short DNA sequences, termed CpG islands, which typically contain around 5–10 CpGs per 100 bp, and up to 80% of CpG islands is localized in noncoding regions that mainly contribute to the global methylation status [12]. LINE-1 sequences, accounting for ≈18% of human genome, are widely used as a surrogate marker of global DNA methylation [13,14,15,16]
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