Role of epigenetic mechanisms in the development of chronic complications of diabetes

Wegner, Małgorzata; Neddermann, Daniel; Pioruńska-Stolzmann, Maria; Jagodzińśki, Paweł P.

doi:10.1016/j.diabres.2014.03.019

Cited by 62 publications

(56 citation statements)

References 98 publications

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“…We have observed a moderate decrease in deoxy-glucose uptake in the chronically treated mature endothelial monolayers as a result of downregulation of total GLUT3 and cell surface GLUT1, while no major changes in GLUT mRNA expression were detected. Absence of mRNA changes suggests that direct epigenetic modulation, documented for various genes in hyperglycaemia [68], was not relevant for GLUTs in our study. Alternatively, post-translational regulations may involve changes in palmitoylation [69] or glycosylation, which could modify GLUT localization, stability or activity directly or via interactions with other molecules [70,71].…”

Section: Discussionmentioning

confidence: 68%

Transendothelial glucose transport is not restricted by extracellular hyperglycaemia

Tumova

Kerimi

Porter

et al. 2016

Vascular Pharmacology

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Endothelial cells are routinely exposed to elevated glucose concentrations post-prandially in healthy individuals and permanently in patients with metabolic syndrome and diabetes, and so we assessed their sugar transport capabilities in response to high glucose. In human umbilical vein (HUVEC), saphenous vein, microdermal vessels and aorta, GLUT1 (SLC2A1), GLUT3 (SLC2A3), GLUT6 (SLC2A6), and in microdermal vessels also GLUT12 (SLC2A12), were the main glucose transporters as assessed by mRNA, with no fructose transporters nor SGLT1 (SLC5A1). Uptake of 14 C-fructose was negligible. GLUT1 and GLUT3 proteins were detected in all cell types and were responsible for ~60% glucose uptake in HUVECs, where both GLUT1 and GLUT3, but not GLUT6 siRNA knock-down, reduced the transport. Under shear conditions, GLUT1 protein decreased, GLUT3 increased, and 14 C-deoxy-glucose uptake was attenuated. In high glucose, lipid storage was increased, cell numbers were lower, 14 C-deoxyglucose uptake decreased owing to attenuated GLUT3 protein and less surface GLUT1, and transendothelial transport of glucose increased due to cell layer permeability changes. We conclude that glucose transport by endothelial cells is relatively resistant to effects of elevated glucose. Cells would continue to supply it to the underlying tissues at a rate proportional to the blood glucose concentration, independent of insulin or fructose.

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Section: Discussionmentioning

confidence: 68%

Transendothelial glucose transport is not restricted by extracellular hyperglycaemia

Tumova

Kerimi

Porter

et al. 2016

Vascular Pharmacology

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“…The importance of histone methylation to retinal development has been highlighted in several papers (Kizilyaprak et al 2010;Rao et al 2010). The role of epigenetic modifications in diabetic retinopathy is emerging (Wegner et al 2014); together, these findings indicate the potential utility of epigenetic modifications as therapeutic targets. We are interested in the epigenetic regulation of retinal development through histone modification at critical genetic loci.…”

Section: Introductionmentioning

confidence: 97%

Regulation of Retinal Development via the Epigenetic Modification of Histone H3

Watanabe

Murakami

2015

Retinal Degenerative Diseases

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We are interested in the roles of epigenetic mechanisms in retinal development. By ChIP-qPCR using whole retinal extracts at various developmental stages, we found that the levels of methylation of histones H3K27 and H3K4 and acetylation of histone H3 at specific loci in various genes, which play critical roles in retinal proliferation and differentiation, changed dramatically during retinal development. We next focused on the roles of H3K27 trimethylation in retinal development. Ezh1 and Ezh2 are methyltransferases that act on H3K27, while Jmjd3 and Utx are demethylases. We found that Ezh2 and Jmjd3 were mainly expressed during retinal development, and a loss-of-function of these genes revealed a role for H3K27me3 in the maturation of subsets of bipolar cells. Furthermore, Ezh2 and Jmjd3 regulate H3K27 trimethylation at specific loci within Bhlhb4 and Vsx1, which play critical roles in the differentiation of subsets of bipolar cells. Utx is expressed weakly in retina, and the down-regulation of Utx by sh-RNA in retinal explants suggested that Utx also participates in the maturation of bipolar cells. Ezh1 is expressed weakly in postnatal retina, and the phenotype of Ezh2-knockout retina suggested that Ezh1 plays a role in the methylation of H3K27 in the late phase of retinal differentiation. Taken together, we found that these four genes, which exhibit temporally and spatially unique expression patterns during retinal development, play critical roles in the differentiation of retinal subsets through the regulation of histone H3K27 methylation at critical genetic loci.

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“…Impaired calcium handling, altered metabolism, increased oxidative stress, remodeling of extracellular matrix (ECM), endothelial dysfunction and mitochondrial dysfunction have been found to participate in the pathogenesis of DCM (2,(10)(11)(12)(13)(14). A number of signaling proteins and pathways have been implicated in contributing to the development of DCM, including protein kinase C, nuclear factor-κB, peroxisome proliferator-activated receptor α, phosphatidylinositol 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling pathways (15,16).…”

Section: Introductionmentioning

confidence: 99%

“…As a progressive metabolic disorder, chronic complications occur in the late stage of diabetes, including atherosclerosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy (DCM) (2). Among the vast array of long-term complications associated with diabetes, cardiovascular diseases account for the major cause of morbidity and mortality among the diabetic population worldwide (3)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Role of microRNAs in the pathogenesis of diabetic cardiomyopathy

Liu

2017

Biomedical Reports

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Abstract. The morbidity of diabetes mellitus has been increasing annually. As a progressive metabolic disorder, chronic complications occur in the late stage of diabetes. In addition, cardiovascular diseases account for the major cause of morbidity and mortality among the diabetic population worldwide. Diabetic cardiomyopathy (DCM) is a type of diabetic heart disease. Patients with DCM show symptoms and signs of heart failure while no specific cause, such as coronary disease, hypertension, alcohol consumption, or other structural heart diseases has been identified. The pathogenesis of DCM is complex and has not been well understood until recently. MicroRNAs (miRs) belong to a novel family of highly conserved, short, non-coding, single-stranded RNA molecules that regulate transcriptional and post-transcriptional gene expression. Furthermore, recent studies have demonstrated an association between miRs and DCM. In the current review, the role of miRs in the pathogenesis of DCM is summarized. It was concluded that miRs contribute to the regulation of cardiomyocyte hypertrophy, myocardial fibrosis, cardiomyocyte apoptosis, mitochondrial dysfunction, myocardial electrical remodeling, epigenetic modification and various other pathophysiological processes of DCM. These studies may provide novel insights into targets for prevention and treatment of the disease.

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Role of epigenetic mechanisms in the development of chronic complications of diabetes

Cited by 62 publications

References 98 publications

Transendothelial glucose transport is not restricted by extracellular hyperglycaemia

Transendothelial glucose transport is not restricted by extracellular hyperglycaemia

Regulation of Retinal Development via the Epigenetic Modification of Histone H3

Role of microRNAs in the pathogenesis of diabetic cardiomyopathy

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