Diabetic retinopathy: reversibility of epigenetic modifications and new therapeutic targets.
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ABSTRACT:
SUBMITTER: Zhang X
PROVIDER: S-EPMC5557533 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Diabetic retinopathy remains one of the most debilitating chronic complications, but despite extensive research in the field, the exact mechanism(s) responsible for how retina is damaged in diabetes remains ambiguous. Many metabolic pathways have been implicated in its development, and genes associated with these pathways are altered. Diabetic environment also facilitates epigenetics modifications, which can alter the gene expression without permanent changes in DNA sequence. The role of epigenetics in diabetic retinopathy is now an emerging area, and recent work has shown that genes encoding mitochondrial superoxide dismutase (Sod2) and matrix metalloproteinase-9 (MMP-9) are epigenetically modified, activates of epigenetic modification enzymes, histone lysine demethylase 1 (LSD1), and DNA methyltransferase are increased, and the micro RNAs responsible for regulating nuclear transcriptional factor and VEGF are upregulated. With the growing evidence of epigenetic modifications in diabetic retinopathy, better understanding of these modifications has potential to identify novel targets to inhibit this devastating disease. Fortunately, the inhibitors and mimics targeted towards histone modification, DNA methylation, and miRNAs are now being tried for cancer and other chronic diseases, and better understanding of the role of epigenetics in diabetic retinopathy will open the door for their possible use in combating this blinding disease.
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Project description:Retinal pigment epithelium (RPE) is an important component of the outer blood-retinal barrier and plays a critical role in maintaining retinal homeostasis. Alterations in RPE can be detected during the early stages of diabetic retinopathy (DR). However, the molecular mechanisms underlying these early changes remain unclear. We investigated the molecular changes induced in the RPE by high glucose concentrations by constructing a high glucose-induced ARPE-19 cell injury model simulating the DR environment in vitro. Proteomic analysis was conducted to measure differences in protein expression between cells treated with normal (5 mM) and high (25 mM) glucose concentrations, and bioinformatics techniques were used to analyze the mechanism of action. The results of the proteomic analyses were validated using western blotting. High glucose levels inhibited the proliferation of ARPE-19 cells. We identified 88 upregulated proteins and 114 downregulated proteins. Six of these proteins were selected for further validation. Changes in the proteome mainly affected the lysosome and cell cycle pathways. Proteomic differences between ARPE-19 cells treated with normal and high glucose concentrations indicate that damage to the RPE in DR may be caused by specific mechanisms. Our study verified protein changes in ARPE-19 cells in a high-glucose environment and may provide new strategies for understanding the molecular mechanisms underlying DR.
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Project description:Diabetic retinopathy is a common microvascular complication of diabetes mellitus. It affects a substantial proportion of US adults over age 40. The condition is a leading cause of visual loss. Much attention has been given to expanding the role of current treatments along with investigating various novel therapies and drug delivery methods. In the treatment of diabetic macular edema (DME), intravitreal pharmacotherapies, especially anti-vascular endothelial growth factor (anti-VEGF) agents, have gained popularity. Currently, anti-VEGF agents are often used as first-line agents in center-involved DME, with recent data suggesting that among these agents, aflibercept leads to better visual outcomes in patients with worse baseline visual acuities. While photocoagulation remains the standard treatment for proliferative diabetic retinopathy (PDR), recent FDA approvals of ranibizumab and aflibercept in the management of diabetic retinopathy associated with DME may suggest a potential for pharmacologic treatments of PDR as well. Novel therapies, including small interfering RNAs, chemokines, kallikrein-kinin inhibitors, and various anti-angiogenic agents, are currently being evaluated for the management of diabetic retinopathy and DME. In addition to these strategies, novel drug delivery methods such as sustained-release implants and refillable reservoir implants are either under active evaluation or have recently gained FDA approval. This review provides an update on the novel developments in the treatment of diabetic retinopathy.
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Project description:Diabetic retinopathy remains the major cause of blindness among working age adults. Although a number of metabolic abnormalities have been associated with its development, due to complex nature of this multi-factorial disease, a link between any specific abnormality and diabetic retinopathy remains largely speculative. Diabetes increases oxidative stress in the retina and its capillary cells, and overwhelming evidence suggests a bidirectional relationship between oxidative stress and other major metabolic abnormalities implicated in the development of diabetic retinopathy. Due to increased production of cytosolic reactive oxygen species, mitochondrial membranes are damaged and their membrane potentials are impaired, and complex III of the electron transport system is compromised. Suboptimal enzymatic and nonenzymatic antioxidant defense system further aids in the accumulation of free radicals. As the duration of the disease progresses, mitochondrial DNA (mtDNA) is damaged and the DNA repair system is compromised, and due to impaired transcription of mtDNA-encoded proteins, the integrity of the electron transport system is encumbered. Due to decreased mtDNA biogenesis and impaired transcription, superoxide accumulation is further increased, and the vicious cycle of free radicals continues to self-propagate. Diabetic milieu also alters enzymes responsible for DNA and histone modifications, and various genes important for mitochondrial homeostasis, including mitochondrial biosynthesis, damage and antioxidant defense, undergo epigenetic modifications. Although antioxidant administration in animal models has yielded encouraging results in preventing diabetic retinopathy, controlled longitudinal human studies remain to be conducted. Furthermore, the role of epigenetic in mitochondrial homeostasis suggests that regulation of such modifications also has potential to inhibit/retard the development of diabetic retinopathy.
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Project description:To study Hyperhomocysteinemia (HHcy)-induced epigenetic modifications as potential mechanisms of blood retinal barrier (BRB) dysfunction, retinas isolated from three- week-old mice with elevated level of Homocysteine (Hcy) due to lack of the enzyme cystathionine β-synthase (cbs-/- , cbs+/- and cbs+/+ ), human retinal endothelial cells (HRECs), and human retinal pigmented epithelial cells (ARPE-19) treated with or without Hcy were evaluated for (1) histone deacetylases (HDAC), (2) DNA methylation (DNMT), and (3) miRNA analysis. Differentially expressed miRNAs in mice with HHcy were further compared with miRNA analysis of diabetic mice retinas (STZ) and miRNAs within the exosomes released from Hcy-treated RPEs. Differentially expressed miRNAs were further evaluated for predicted target genes and associated pathways using Ingenuity Pathway Analysis. HHcy significantly increased HDAC and DNMT activity in HRECs, ARPE-19, and cbs mice retinas, whereas inhibition of HDAC and DNMT decreased Hcy-induced BRB dysfunction. MiRNA profiling detected 127 miRNAs in cbs+/- and 39 miRNAs in cbs-/- mice retinas, which were significantly differentially expressed compared to cbs+/+ . MiRNA pathway analysis showed their involvement in HDAC and DNMT activation, endoplasmic reticulum (ER), and oxidative stresses, inflammation, hypoxia, and angiogenesis pathways. Hcy-induced epigenetic modifications may be involved in retinopathies associated with HHcy, such as age-related macular degeneration and diabetic retinopathy.
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Project description:Type 2 diabetes accounts for 90% of the population with diabetes, and these patients are generally obese and hyperlipidemic. In addition to hyperglycemia, hyperlipidemia is also closely related with diabetic retinopathy. The aim was to investigate retinopathy in a model closely mimicking the normal progression and metabolic features of the population with type 2 diabetes and elucidate the molecular mechanism. Retinopathy was evaluated in rats fed a 45% kcal as fat diet for 8 weeks before administering streptozotocin, 30 mg/kg body weight (T2D), and compared with age- and duration-matched type 1 diabetic rats (T1D) (60 mg/kg streptozotocin). The role of epigenetic modifications in mitochondrial damage was evaluated in retinal microvasculature. T2D rats were obese and severely hyperlipidemic, with impaired glucose and insulin tolerance compared with age-matched T1D rats. While at 4 months of diabetes, T1D rats had no detectable retinopathy, T2D rats had significant retinopathy, their mitochondrial copy numbers were lower, and mtDNA and Rac1 promoter DNA methylation was exacerbated. At 6 months, retinopathy was comparable in T2D and T1D rats, suggesting that obesity exaggerates hyperglycemia-induced epigenetic modifications, accelerating mitochondrial damage and diabetic retinopathy. Thus, maintenance of good lifestyle and BMI could be beneficial in regulating epigenetic modifications and preventing/retarding retinopathy in patients with diabetes.
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Project description:Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications-histone methylation, acetylation and crotonylation-in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio- and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.
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Project description: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.
| S-EPMC5499690 | biostudies-literature
Project description:Despite the existence of treatment for diabetes, inadequate metabolic control triggers the appearance of chronic complications such as diabetic retinopathy. Diabetic retinopathy is considered a multifactorial disease of complex etiology in which oxidative stress and low chronic inflammation play essential roles. Chronic exposure to hyperglycemia triggers a loss of redox balance that is critical for the appearance of neuronal and vascular damage during the development and progression of the disease. Current therapies for the treatment of diabetic retinopathy are used in advanced stages of the disease and are unable to reverse the retinal damage induced by hyperglycemia. The lack of effective therapies without side effects means there is an urgent need to identify an early action capable of preventing the development of the disease and its pathophysiological consequences in order to avoid loss of vision associated with diabetic retinopathy. Therefore, in this review we propose different therapeutic targets related to the modulation of the redox and inflammatory status that, potentially, can prevent the development and progression of the disease.
| S-EPMC8472497 | biostudies-literature
Project description:BackgroundAberrant epigenetic modifications such as DNA methylation may contribute to the pathogenesis of DR. We aimed at elucidating the role of novel DNA methylation modifications in diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM) using an extreme phenotypic design.Methods/resultsTwo consecutive studies were conducted. A cross-sectional study using an extreme phenotypic design was conducted to identify rare methylation modifications that might contribute to DR pathogenesis. A 2-year longitudinal nested case-control study was conducted to validate the results and assess whether these novel methylation modifications could be used as biomarkers for predicting DR onset. A large number of differentially methylated CpG sites were identified in the cross-sectional study, and two (cg12869254 and cg04026387) corresponding to known genes were replicated in the longitudinal study. Higher methylation of cg12869254 significantly correlated with macular RNFL thinning in the superior and nasal subregions, and that of cg04026387 correlated with reduced deep capillary plexus VD in the superior and inferior subregions after adjusting for covariates.ConclusionsCg12869254 and cg04026387 hypermethylation may complement the known risk factors that contribute to the pathogenesis of DR and as novel biomarkers for disease prediction.
| S-EPMC9623976 | biostudies-literature