Mitochondria DNA Replication and DNA Methylation in the Metabolic Memory Associated with Continued Progression of Diabetic Retinopathy

Tewari, Shikha; Zhong, Qing; Santos, Júlia Matzenbacher dos; Kowluru, Renu A.

doi:10.1167/iovs.12-9732

Cited by 107 publications

(111 citation statements)

References 25 publications

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“…Hyperglycaemic memory has mainly been studied in shortterm (cell culture) or long-term animal models, such as the studies by Kowluru [5]. Therefore, the aim of this study was to evaluate a novel model of intermediate-term hyperglycaemic memory using islet transplantation to enable the study of subsequent early structural alterations in the neurovascular unit of the retina in diabetic retinopathy.…”

Section: Introductionmentioning

confidence: 99%

Hyperglycaemic memory affects the neurovascular unit of the retina in a diabetic mouse model

et al. 2017

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Aims/hypothesis The aim of this study was to evaluate damage to the neurovascular unit in a mouse model of hyperglycaemic memory. Methods A streptozotocin-induced mouse model of diabetes (C57BL/6J background) received insulin-releasing pellets and pancreatic islet-cell transplantation. Damage to the neurovascular unit was studied by quantitative retinal morphometry for microvascular changes and microarray analysis, with subsequent functional annotation clustering, for changes of the retinal genome.

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Section: Introductionmentioning

confidence: 99%

Hyperglycaemic memory affects the neurovascular unit of the retina in a diabetic mouse model

et al. 2017

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“…Because DNA-me can be inherited during cell division, persistence of DNA-me changes might reflect metabolic history. This hypothesis is supported by experimental models showing persistent DNA-me changes (global or at specific loci related to complications) in zebrafish with hyperglycemia (35), diabetic patient-derived fibroblasts (36), and retinas from diabetic rats under poor glucose control (37). However, the cause-effect relationship between epigenetics and human metabolic memory is not yet fully clear.…”

mentioning

confidence: 97%

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Chen

Miao

Paterson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

196

185

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We examined whether persistence of epigenetic DNA methylation (DNA-me) alterations at specific loci over two different time points in people with diabetes are associated with metabolic memory, the prolonged beneficial effects of intensive vs. conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term followup Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We compared DNA-me profiles in genomic DNA of whole blood (WB) isolated at EDIC Study baseline from 32 cases (DCCT conventional therapy group subjects showing retinopathy or albuminuria progression by EDIC Study year 10) vs. 31 controls (DCCT intensive therapy group subjects without complication progression by EDIC year 10). DNA-me was also profiled in blood monocytes (Monos) of the same patients obtained during EDIC Study years 16-17. In WB, 153 loci depicted hypomethylation, and 225 depicted hypermethylation, whereas in Monos, 155 hypomethylated loci and 247 hypermethylated loci were found (fold change ≥1.3; P < 0.005; cases vs. controls). Twelve annotated differentially methylated loci were common in both WB and Monos, including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications. A set of differentially methylated loci depicted similar trends of associations with prior HbA1c in both WB and Monos. In vitro, high glucose induced similar persistent hypomethylation at TXNIP in cultured THP1 Monos. These results show that DNA-me differences during the DCCT persist at certain loci associated with glycemia for several years during the EDIC Study and support an epigenetic explanation for metabolic memory.T he landmark Diabetes Control and Complications Trial (DCCT; 1983-1993 clearly showed that intensive (INT) glycemic control profoundly reduces the development and progression of microvascular complications in type 1 diabetes (T1D). The DCCT participants were subsequently followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study (1994 to present), during which all subjects were advised to practice INT treatment. Surprisingly, those previously assigned to conventional (CONV) therapy continued to develop complications, such as nephropathy, retinopathy, and macrovascular diseases, at significantly higher rates than the previous INT therapy group, despite nearly similar HbA1c levels during the EDIC Study (1-3). This persistence of benefit from early application of INT therapy, called "metabolic memory," is an enigma in the field of T1D: recent studies have suggested the involvement of epigenetic mechanisms (4-9).Epigenetics is the study of mostly heritable changes in gene expression and phenotype that occur without alterations in the underlying DNA sequence. Epigenetic states are affected by environmental factors, such as aberrant nutrition and metabolic states (4, 6-8, 10). DNA methylation (DNA-me; the classic epigenetic mark) and posttranslational modifications (PTMs) of histo...

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“…In a casecontrolled study of 168 patients with type 2 DM, the global DNA methylation status was shown to be associated with DR. Additionally, the DNA methylation status exhibited a strong correlation with the progression of DR [71,72]. Apart from the increased activity of Dnmts in the retina and its capillary cells [73], histone-modifying machinery is also affected in diabetes.…”

Section: The Role Of Epigenetics In the Pathogenesis Of Diabetic Retimentioning

confidence: 99%

“…Due to the lack of supporting histones, and the close proximity to the superoxide-generating electron transport chain, mtDNA is prone to oxidative damage [111,112]. In diabetes, the activity of retinal Dnmts is increased, and the mtDNA replication enzyme, the polymerase γ-1 (POLG1) gene, is hypermethylated and its binding at the D-loop is impaired, resulting in decreased mtDNA biogenesis [73].…”

Section: The Role Of Epigenetics In the Pathogenesis Of Diabetic Retimentioning

confidence: 99%

Oxidative Stress Biomarkers for Diabetic Retinopathy and Medical Management Affecting Oxidative Stress

Cilenšek¹,

Ramuš²,

Petrovič³

et al. 2016

Role of Biomarkers in Medicine

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Changes in dietary habits and lifestyles associated with rapid economic growth have dramatically increased the incidence of diabetes and related vascular complications. Diabetic retinopathy (DR), a microvascular complication of diabetes, is associated with both environmental and genetic factors. Several metabolic abnormalities are implicated in its pathogenesis; however, the exact mechanism remains to be determined. Among them, oxidative stress is expected to play an important role.Environmental, genetic, and epigenetic factors affecting the oxidative stress responsible for DR are reviewed in this paper. The knowledge about genetic biomarkers of DR is quite extensive, whereas the awareness about epigenetics and epigenetic markers is only beginning to be understood.Modulation of epigenetic changes by pharmaceutical means may provide a potential strategy to retard the progression of DR. In addition to the intense medical management, these strategies include dietary measures (antioxidants) and the introduction of epigenetic drugs, such as inhibitors of DNA methylation and histone demethylases.

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Mitochondria DNA Replication and DNA Methylation in the Metabolic Memory Associated with Continued Progression of Diabetic Retinopathy

Cited by 107 publications

References 25 publications

Hyperglycaemic memory affects the neurovascular unit of the retina in a diabetic mouse model

Hyperglycaemic memory affects the neurovascular unit of the retina in a diabetic mouse model

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Oxidative Stress Biomarkers for Diabetic Retinopathy and Medical Management Affecting Oxidative Stress

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