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1.
J Diabetes Res ; 2021: 7059139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33490285

RESUMO

Background: Vascular endothelial growth factor (VEGF) gene polymorphisms have been shown to be associated with the risk of diabetic retinopathy (DR), but the results were inconsistent. The aim of this study was to systematically assess the associations between VEGF gene polymorphisms and different types of DR (nonproliferative DR and proliferative DR). Methods: Electronic databases PubMed, Embase, Web of Science, CNKI, and WANFANG DATA were searched for articles on the associations between VEGF gene polymorphisms and different types of DR up to November 6, 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and subgroup analyses were conducted by ethnicity. Sensitivity analysis was conducted to assess the stability of the results. Publication bias was assessed by using the Egger regression asymmetry test and visualization of funnel plots. A systematic review was conducted for polymorphisms with a high degree of heterogeneity (I 2 > 75%) or studied in only one study. Results: A total of 13 and 18 studies analyzed the associations between VEGF SNPs and nonproliferative DR (NPDR) as well as proliferative DR (PDR), respectively. There were significant associations between rs2010963 and NPDR in Asian (dominant model: OR = 1.29, 95%CI = 1.04 - 1.60); and rs2010963 is associated with PDR in total population (dominant model: OR = 1.20, 95%CI = 1.03 - 1.41), either Asian (recessive model: OR = 1.57, 95%CI = 1.04 - 2.35) or Caucasian (recessive model: OR = 1.83, 95%CI = 1.28 - 2.63). Rs833061 is associated with PDR in Asian (recessive model: OR = 1.58, 95%CI = 1.11 - 2.26). Rs699947 is associated with NPDR in the total population (dominant model: OR = 2.04, 95%CI = 1.30 - 3.21) and associated with PDR in Asian (dominant model: OR = 1.72, 95%CI = 1.05 - 2.84). Conclusions: Rs2010963, rs833061, and rs699947 are associated with NPDR or PDR, which may be involved in the occurrence and development of DR.


Assuntos
Retinopatia Diabética/genética , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/classificação , Retinopatia Diabética/epidemiologia , Feminino , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Vitreorretinopatia Proliferativa/epidemiologia , Vitreorretinopatia Proliferativa/genética
3.
Gene ; 760: 144992, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32721474

RESUMO

BACKGROUND AND AIM: Diabetic retinopathy is a severe diabetic complication and a major cause of blindness. In this study, we explored the role of circ_0001879 in retinal vascular dysfunction under diabetic conditions. METHODS: Human retinal microvascular endothelial cells (HRMECs) were divided into normal glucose group (NG, 5.5 mmol/L d-glucose), high glucose group (HG, 25 mmol/L d-glucose), and osmotic control group (5.5 mmol/L d-glucose + 19.5 mmol/L mannitol). The expression of circ_0001879 and miR-30-3p was assessed via qRT-PCR. The circ_0001879/miR-30-3p roles in retinal vascular dysfunction were investigated through Cell Counting Kit-8 and Transwell assay. Bioinformatics analysis and luciferase reporter assays were applied to examine interactions between circ_0001879 and miR-30-3p in HRMECs. RESULTS: The relative circ_0001879 expression was remarkably increased in diabetic retinas group than that in the control group. Silencing circ_0001879 suppressed the proliferation and migration of HRMECs under high-glucose conditions. In addition, circ_0001879 acted as a binding platform and miRNA sponge for miR-30-3p. Circ_0001879 modulated the function of HRMECs via targeting miR-30-3p. CONCLUSION: Silencing circ_0001879 inhibited the proliferation and migration of HRMECs under high-glucose conditions via modulating miR-30-3p, which might shed new light on a novel potentially marker and molecular therapeutic target for diabetic retinopathy.


Assuntos
Retinopatia Diabética/patologia , Glucose/administração & dosagem , MicroRNAs/genética , Vasos Retinianos/patologia , Animais , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glucose/metabolismo , Humanos , Masculino , MicroRNAs/metabolismo , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo
4.
Vasc Health Risk Manag ; 16: 241-248, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606720

RESUMO

Aim: Type 2 diabetes (T2D), as a major cause of morbidity and mortality, is predicted to have a prevalence of 629 million by 2045. As diabetic patients show considerable inter-individual variation in response to antidiabetic treatment, this study aimed to investigate the gene polymorphism of cytochrome P450 as well as the effectiveness and safety of glibenclamide and gliclazide for different genotypes of CYP2C9. Besides, the chronic side effects of T2D including retinal microvasculature complications or retinopathy and renal dysfunction due to nephropathy in different genotypes were considered. Patients and Methods: The participants including 80 T2D patients treated with glibenclamide or gliclazide were recruited from university hospitals of Ahvaz Jundishpur University of Medical Sciences, Ahvaz, in the southwest of Iran. Blood samples were collected from the patients at 2.5h after the morning dose of glibenclamide and 12h after the last dose of gliclazide. Genotyping from the extracted DNA was, then, performed using PCR-RFLP. The plasma level of glibenclamide and gliclazide was, in turn, measured by the reverse-phase high-pressure liquid chromatography. Results: The results showed that the wild-type allele, i.e., CYP2C9*1, occurred in the highest frequency (0.8), while the frequency rates of the mutant allele, i.e., CYP2C9*2 and CYP2C9*3, were 0.15 and 0.05, respectively. Moreover, no significant association was found between any of the genotypes as well as the clinical and biochemical characteristics of the patients. The findings also showed that the plasma level of sulfonylureas (i.e., glibenclamide and gliclazide) was the highest in the patients with the CYP2C9*3 allele. It was also found that 75.9% of the patients with variant genotypes had experienced hypoglycemia events. Furthermore, in the absence of wild type allele, a significant increase was observed in retinopathy (p=0.039) and nephropathy (p=0.05). Conclusion: The findings can provide guidelines for the optimal management of the treatment protocols with sulfonylurea intended to control the T2D complications.


Assuntos
Glicemia/efeitos dos fármacos , Citocromo P-450 CYP2C9/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/genética , Retinopatia Diabética/genética , Gliclazida/uso terapêutico , Glibureto/uso terapêutico , Hipoglicemiantes/uso terapêutico , Variantes Farmacogenômicos , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/diagnóstico , Retinopatia Diabética/diagnóstico , Feminino , Frequência do Gene , Gliclazida/efeitos adversos , Gliclazida/sangue , Glibureto/efeitos adversos , Glibureto/sangue , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/genética , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento
5.
PLoS One ; 15(7): e0235541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692745

RESUMO

The main objective of this pilot study was to identify circulatory microRNAs in aqueous or plasma that were reflecting changes in vitreous of diabetic retinopathy patients. Aqueous, vitreous and plasma samples were collected from a total of 27 patients undergoing vitreoretinal surgery: 11 controls (macular pucker or macular hole patients) and 16 with diabetes mellitus(DM): DM-Type I with proliferative diabetic retinopathy(PDR) (DMI-PDR), DM Type II with PDR(DMII-PDR) and DM Type II with nonproliferative DR(DMII-NPDR). MicroRNAs were isolated using Qiagen microRNeasy kit, quantified on BioAnalyzer, and profiled on Affymetrix GeneChip miRNA 3.0 microarrays. Data were analyzed using Expression Console, Transcriptome Analysis Console, and Ingenuity Pathway Analysis. The comparison analysis of circulatory microRNAs showed that out of a total of 847 human microRNA probes on the microarrays, common microRNAs present both in aqueous and vitreous were identified, and a large number of unique microRNA, dependent on the DM type and severity of retinopathy. Most of the dysregulated microRNAs in aqueous and vitreous of DM patients were upregulated, while in plasma, they were downregulated. Dysregulation of miRNAs in aqueous did not appear to be a good representative of the miRNA abundance in vitreous, or plasma, although a few potential candidates for common biomarkers stood out: let-7b, miR-320b, miR-762 and miR-4488. Additionally, each of the DR subtypes showed miRNAs that were uniquely dysregulated in each fluid (i.e. aqueous: for DMII-NPDR was miR-455-3p; for DMII-PDR was miR-296, and for DMI-PDR it was miR-3202). Pathway analysis identified TGF-beta and VEGF pathways affected. The comparative profiling of circulatory miRNAs showed that a small number of them displayed differential presence in diabetic retinopathy vs. controls. A pattern is emerging of unique molecular microRNA signatures in bodily fluids of DR subtypes, offering promise for the use of ocular fluids and plasma for diagnostic and therapeutic purposes.


Assuntos
Humor Aquoso/metabolismo , Retinopatia Diabética/metabolismo , MicroRNAs/metabolismo , Corpo Vítreo/metabolismo , Retinopatia Diabética/sangue , Retinopatia Diabética/genética , Regulação da Expressão Gênica , Humanos , MicroRNAs/sangue
6.
Vascul Pharmacol ; 131: 106761, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32585189

RESUMO

AIMS: Diabetes-induced retinal vascular cell death aggravates diabetic retinopathy (DR) to the proliferative stage and blindness. Pericytes play a crucial role in retinal capillaries survival, stability, and angiogenesis. Ephrin-B2 is a tyrosine kinase that regulates pericytes/endothelial cells communication during angiogenesis; yet, its role in DR is still unclear. We hypothesize that diabetes increases Ephrin-B2 signaling in pericytes, which contributes to inflammation and retinal vascular cell death. METHODS: Selective inhibition of the Ephrin-B2 expression in the retinal pericytes was achieved using an intraocular injection of adeno-associated virus (AAV) with a specific pericyte promotor. Vascular death was determined by retinal trypsin digest. Pathological angiogenesis was assessed using the oxygen-induced retinopathy model in pericyte-Ephrin-B2 knockout mice, wild type, and wild type injected with AAV. Angiogenic properties, inflammatory, and apoptotic markers were measured in human retinal pericytes (HRP) grown under diabetic conditions. KEY FINDING: Diabetes significantly increased the expression of Ephrin-B2, inflammatory, and apoptotic markers in the diabetic retinas and HRP. These effects were prevented by silencing Ephrin-B2 in HRP. Moreover, Ephrin-B2 silencing in retinal pericytes decreased pathological angiogenesis and acellular capillaries formation in diabetic retinas. SIGNIFICANCE: Increased Ephrin-B2 expression in the pericytes contributed to diabetes-induced retinal inflammation and vascular death. These results identify pericytes-Ephrin-B2 as a therapeutic target for DR.


Assuntos
Apoptose , Retinopatia Diabética/metabolismo , Efrina-B2/metabolismo , Pericitos/metabolismo , Neovascularização Retiniana/metabolismo , Vasos Retinianos/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/etiologia , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Efrina-B2/deficiência , Efrina-B2/genética , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pericitos/patologia , Ratos Wistar , Neovascularização Retiniana/etiologia , Neovascularização Retiniana/genética , Neovascularização Retiniana/patologia , Vasos Retinianos/patologia , Transdução de Sinais , Estreptozocina
7.
Life Sci ; 256: 117888, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32497630

RESUMO

AIMS: The dysregulation of circular RNAs (circRNAs) has been implicated in the progression of diabetic retinopathy (DR). This study aims to explore the role and underlying mechanism of hsa_circ_0081108 (circCOL1A2) in DR. MATERIALS AND METHODS: circCOL1A2, vascular endothelial growth factor (VEGF) and miR-29b expression levels in human retinal microvascular endothelial cells (hRMECs) were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blotting. The biological functions of hRMECs were evaluated by MTT, transwell, tube formation, and vascular permeability assays, respectively. The interaction between miR-29b and circCOL1A2/VEGF was determined by dual luciferase assay. The release of VEGF was examined by ELISA. The in vivo role of circCOL1A2 was further verified in streptozotocin (STZ)-induced DR in mice. The pathological changes and VEGF expression in retinal tissues were detected by hematoxylin and eosin (HE) and immunohistochemical staining. KEY FINDINGS: High glucose (HG) challenge led to increased circCOL1A2, VEGF, MMP-2, MMP-9 levels, but decreased miR-29b level in hRMECs. In addition, circCOL1A2 sponged miR-29b to promote VEGF expression. Silencing of circCOL1A2 inhibited HG-induced proliferation, migration, angiogenesis and vascular permeability of hRMECs via enhancing miR-29b expression. Moreover, circCOL1A2/miR-29b axis participated in HG-induced increase in angiogenesis-related protein expression. Finally, circCOL1A2 knockdown suppressed angiogenesis via regulating miR-29b/VEGF axis in DR mice. SIGNIFICANCE: circCOL1A2 facilities angiogenesis during the pathological progression of DR via regulating miR-29b/VEGF axis, suggesting that targeting circCOL1A2 may be a potential treatment for DR.


Assuntos
Retinopatia Diabética/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Neovascularização Patológica/genética , RNA Circular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Sequência de Bases , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Glucose/toxicidade , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Microvasos/patologia , Modelos Biológicos , RNA Circular/genética , Retina/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Acta Diabetol ; 57(9): 1111-1116, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32447557

RESUMO

AIMS: Long non-coding RNA (lncRNA) VIM Antisense RNA 1 (VIM-AS1) has been reported to be correlated with type 2 diabetes (T2D) susceptibility, while the roles of this lncRNA in T2D and its complications remain unclear. This study aimed to explore the role of VIM-AS1 in diabetic retinopathy (DR). METHODS: Gene expression levels in both human specimens and in vitro cultivated cells were determined by qPCR and western blot. Overexpression experiments were performed to analyze gene interactions. Cell apoptosis after transfections was detected by cell apoptosis assay. RESULTS: We found that VIM-AS1 was significantly downregulated in T2D patients in comparison with that in healthy controls. Specifically, the expression levels of VIM-AS1 were lowest among T2D patients complicated with DR. Bioinformatics analysis showed that VIM-AS1 can interact with microRNA 29 (miR-29), which is a critical player in high glucose-induced apoptosis of human retinal pigment epithelial cells (RPEs). Dual-luciferase assay also revealed the direct interaction between them. High glucose treatment led to upregulated miR-29 and downregulated VIM-AS1. However, overexpression of VIM-AS1 and miR-29 did not affect the expression of each other. Cell apoptosis analysis showed that overexpression of VIM-AS1 reduced the enhancing effects of miR-29 overexpression on RPEs cell proliferation. CONCLUSIONS: Therefore, VIM-AS1 may sponge miR-29 to participate in DR.


Assuntos
Retinopatia Diabética/genética , MicroRNAs/genética , Interferência de RNA/fisiologia , RNA Longo não Codificante/fisiologia , Adulto , Idoso , Apoptose/genética , Estudos de Casos e Controles , Proliferação de Células/genética , Células Cultivadas , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Retinopatia Diabética/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
9.
Nat Rev Nephrol ; 16(7): 377-390, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32398868

RESUMO

Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.


Assuntos
Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Complicações do Diabetes/etiologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/genética , Retinopatia Diabética/etiologia , Retinopatia Diabética/genética , Humanos
10.
Curr Diab Rep ; 20(7): 22, 2020 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-32415508

RESUMO

PURPOSE OF REVIEW: Diabetic retinopathy (DR), a leading cause of visual impairment in the developed country, is characterized by vascular lesions and neuronal damage of the retina. Treatment options for this condition are currently limited. The advent of therapy targeting vascular endothelial growth factor (VEGF) demonstrated significant benefits to patients with DR. However, this treatment is limited by its short half-life and requirement for frequent invasive intravitreal injections. In addition, many patients failed to achieve clinically significant improvement in visual function. Gene therapy has the potential to provide an alternative treatment for DR with distinct advantages, such as longer therapeutic effect, less injection frequency, ability to intervene at disease onset, and potentially fewer side effects. RECENT FINDINGS: Strategies for gene therapy in DR, stemming from the current understanding of the disease pathogenesis, focus on the inhibition of neovascularization and protection of neurovascular degeneration in the retina. Studies with promising results have mainly focussed on animal models due to efficacy and safety concerns, despite a number of successful preclinical studies using adeno-associated virus-mediated transduction to treat both vascular dysfunction and neuronal degeneration. With the optimization of delivery vectors, transgene regulation, and outcome measure, gene therapy will potentially become available for patients with DR. This review provides an update on the current strategies utilized in DR gene therapy research. Several barriers to the clinical application of gene therapy for DR are highlighted, and future directions for this research are proposed.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Animais , Retinopatia Diabética/genética , Retinopatia Diabética/terapia , Terapia Genética , Humanos , Neovascularização Patológica , Retina , Fator A de Crescimento do Endotélio Vascular
11.
Gene ; 747: 144653, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32259630

RESUMO

Diabetic retinopathy (DR) is a frequent complication of diabetes and it can lead to visual impairment and blindness. However, the mechanism of their regulation remains little known. circRNAs can function as crucial competing endogenous RNA, which can sponge corresponding miRNAs and affect mRNA expression in various diseases, including DR. In our current research, we observed that circRNA_0084043 was elevated in high glucose (HG)-incubated ARPE-19 cells. Then, we focused on whether and how circRNA_0084043 participated in retinal vascular dysfunction under conditions diabetes. Apoptosis, inflammation and oxidative stress are hallmark of DR progression. This work was aimed to investigate the signaling mechanisms of circRNA_0084043 in these pathogenesis of DR. We discovered loss of circRNA_0084043 significantly increased cell survival and repressed HG-triggered apoptosis. In addition, knockdown of circRNA_0084043 remarkably reduced oxidative stress as evidenced by the down-regulated malondialdehyde (MDA) content, enhanced activities of Super Oxide Dismutase (SOD) and Glutathione peroxidase (GSH-PX). Addition, silence of circRNA_0084043 effectively restrained HG-stimulated inflammation as proved by repressing inflammatory cytokines Tumor Necrosis Factor α (TNF-α), Interleukin 6 (IL-6) and Cox-2 in ARPE-19 cells. Subsequently, we successfully predicted that miR-140-3p was a downstream target of circRNA_0084043, which could be negatively regulated by circRNA_0084043. Mechanistically, loss of miR-140-3p abrogated the beneficial effects of circRNA_0084043 siRNA on ARPE-19 cells. Transforming Growth Factor alpha (TGFA) can exhibit a role in multiple diseases. Taken these together, these data demonstrated that loss of circRNA_0084043 depressed HG-induced damage via sponging miR-140-3p and regulating TGFA.


Assuntos
Retinopatia Diabética/genética , Progressão da Doença , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , MicroRNAs/metabolismo , RNA Circular/genética , Epitélio Pigmentado da Retina/patologia , Fator de Crescimento Transformador alfa/genética , Apoptose/efeitos dos fármacos , Sequência de Bases , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/toxicidade , Humanos , Inflamação/patologia , MicroRNAs/genética , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , RNA Circular/metabolismo , Fator de Crescimento Transformador alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
12.
Sci Rep ; 10(1): 6655, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313015

RESUMO

Retinopathy continues to progress even when diabetic patients try to control their blood sugar, but the molecular mechanism of this 'metabolic memory' phenomenon remains elusive. Retinal mitochondria remain damaged and vicious cycle of free radicals continues to self-propagate. DNA methylation suppresses gene expression, and diabetes activates DNA methylation machinery. Our aim was to investigate the role of DNA methylation in continued compromised mitochondrial dynamics and genomic stability in diabetic retinopathy. Using retinal endothelial cells, incubated in 20 mM glucose for four days, followed by 5 mM glucose for four days, and retinal microvessels from streptozotocin-induced diabetic rats in poor glycemia for four months, followed by normal glycemia for four additional months, DNA methylation of mitochondrial fusion and mismatch repair proteins, Mfn2 and Mlh1 respectively, was determined. Retinopathy was detected in trypsin-digested microvasculature. Re-institution of good glycemia had no beneficial effect on hypermethylation of Mfn2 and Mlh1 and retinal function (electroretinogram), and the  retinopathy continued to progress. However, intervention of good glycemia directly with DNA methylation inhibitors (Azacytidine or Dnmt1-siRNA), prevented Mfn2 and Mlh1 hypermethylation, and ameliorated retinal dysfunction and diabetic retinopathy. Thus, direct regulation of DNA methylation can prevent/reverse diabetic retinopathy by maintaining mitochondrial dynamics and DNA stability, and prevent retinal functional damage.


Assuntos
Azacitidina/farmacologia , DNA Mitocondrial/genética , Diabetes Mellitus Experimental/terapia , Retinopatia Diabética/terapia , Epigênese Genética , Hiperglicemia/terapia , Mitocôndrias/genética , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , DNA Mitocondrial/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Progressão da Doença , Eletrorretinografia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Glucose/efeitos adversos , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Transdução de Sinais , Estreptozocina/administração & dosagem
13.
Acta Diabetol ; 57(8): 937-945, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32125531

RESUMO

AIMS: The influence of genetic factors on the development and progression of diabetic retinopathy is still unclear. Previous studies showed controversial results. We aimed to characterize the relationship between genomic ancestry and self-reported color/race with severe diabetic retinopathy in patients with type 1 diabetes belonging to a highly admixed population. METHODS: This study was a nested case-control based on data collected from a large cross-sectional, nationwide survey conducted in clinics from all five geographic regions of Brazil. For the present study, we included 414 individuals. Cases (n = 176) were considered if they had severe non-proliferative or proliferative diabetic retinopathy, and controls (n = 238) were type 1 diabetes patients without retinopathy, matched for diabetes duration by a range of 5 years. Indirect ophthalmoscopy was performed, and individual genomic ancestry was inferred using a panel of 46 ancestry informative markers. RESULTS: The backward stepwise logistic regression analysis showed that African genomic ancestry (OR 3.9, p = 0.045), HbA1c (OR 1.24, p = 0.001), glomerular filtration rate (OR 0.98, p < 0.001) and hypertension (OR 2.52, p < 0.001) were associated with severe diabetic retinopathy after adjusting for clinical and demographic data. Self-reported color/race was not statistically associated with diabetic retinopathy. CONCLUSIONS: Genomic ancestry, as well as clinical variables such as hypertension, impaired glomerular filtration rate and poor diabetes control (HbA1c), was important risk factor for the development of severe diabetic retinopathy. Further studies are needed, especially in highly admixed populations, to better understand the role of genomic ancestry and possible genes that might be associated with the development and/or progression of diabetic retinopathy.


Assuntos
Diabetes Mellitus Tipo 1/etnologia , Diabetes Mellitus Tipo 1/genética , Retinopatia Diabética/etnologia , Retinopatia Diabética/genética , Grupos Étnicos/genética , Adulto , Brasil/epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Progressão da Doença , Grupos Étnicos/estatística & dados numéricos , Feminino , Predisposição Genética para Doença , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Relações Raciais , Fatores de Risco , Adulto Jovem
14.
Gene ; 741: 144539, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32160960

RESUMO

microRNAs (miRNAs) are involved in the physiological and pathophysiological processes of diabetes and its microvascular and macrovascular complications. Hence, the aim of the study was to investigate whether miR-499-3p played an important role in diabetic retinopathy. Diabetic retinopathy was developed in rats by intraperitoneal injection of streptozocin (STZ), followed by collection of retinal tissues and preparation of retinal cells. Immunohistochemical staining was used to detect expression of interferon alpha 2 (IFNA2). RT-qPCR was used to determine the expression of miR-499-3p. Bioinformatics website and dual luciferase reporter gene assay were used to validate the targeting relationship between miR-499-3p and IFNA2. Gain- and loss-of-function assays were performed to explore the functional roles of aberrantly expressed miR-499-3p and IFNA2 in retinal cell proliferation by MTT, and apoptosis by flow cytometry. In retinal tissues and cells of diabetic rats, IFNA2 expression was reduced, and miR-499-3p expression increased to activate the toll-like receptor 4 (TLR4) signaling pathway. IFNA2 was a target gene of miR-499-3p and negatively regulated by miR-499-3p. Further, downregulated miR-499-3p promoted retinal cell proliferation while suppressing apoptosis to alleviate diabetic retinopathy. All in all, miR-499-3p promoted retinopathy by enhancing activation of the TLR4 signaling pathway, which provides a new therapeutic target for diabetic retinopathy.


Assuntos
Retinopatia Diabética/genética , Interferon-alfa/genética , MicroRNAs/genética , Receptor 4 Toll-Like/genética , Animais , Apoptose/genética , Proliferação de Células/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Ratos , Retina/metabolismo , Retina/patologia , Transdução de Sinais/genética
15.
J Immunol Res ; 2020: 1704631, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190702

RESUMO

Macrophages are involved in angiogenesis, an essential process for organ growth and tissue repair, and could contribute to the pathogenesis of angiogenesis-related diseases such as malignant tumors and diabetic retinopathy. Recently, long noncoding RNAs (lncRNAs) have been proved to be important in cell differentiation, organismal development, and various diseases of pathological angiogenesis. Moreover, it has been indicated that numerous lncRNAs exhibit different functions in macrophage infiltration and polarization and regulate the secretion of inflammatory cytokines released by macrophages. Therefore, the focus of macrophage-related lncRNAs could be considered to be a potential method in therapeutic targeting angiogenesis-related diseases. This review mainly summarizes the roles played by lncRNAs which associated with macrophages in angiogenesis. The possible mechanisms of the regulatory link between lncRNAs and macrophages in various angiogenesis-related diseases were also discussed.


Assuntos
Retinopatia Diabética/genética , Macrófagos/fisiologia , Neoplasias/genética , Neovascularização Patológica/genética , RNA Longo não Codificante/genética , Animais , Citocinas/metabolismo , Retinopatia Diabética/imunologia , Humanos , Neoplasias/imunologia , Neovascularização Patológica/imunologia
16.
Horm Metab Res ; 52(3): 142-148, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32215885

RESUMO

Diabetic retinopathy (DR), a serious microvascular complication of diabetes, is a leading cause of blindness in adults. The pathogenesis of DR involves a variety of tissues and complex mechanisms, such as inflammation, oxidative stress, optic neurodegeneration, and autophagy. Nowadays, microRNAs (miRNAs), a novel group of non-coding small RNAs, have been extensively studied and recognized to play a key role in the pathogenesis of DR through aforementioned pathways. Furthermore, some miRNAs have been proposed as biomarkers that may be utilized to screen for DR. Also, miRNAs are a new therapy for DR. In this review, we summarize several miRNAs and, their roles in the pathogenesis of DR. miRNAs, as potential pharmacological targets for the diabetic retinopathy, may provide new insights for the treatment of DR.


Assuntos
Retinopatia Diabética/genética , MicroRNAs/genética , Animais , Biomarcadores/metabolismo , Retinopatia Diabética/metabolismo , Retinopatia Diabética/terapia , Humanos , MicroRNAs/metabolismo , Estresse Oxidativo
17.
Exp Eye Res ; 193: 107973, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32059976

RESUMO

The purpose of this study was to investigate the role of exosomes derived from platelet-rich plasma (PRP-Exos) in the regulation of the fibrogenic activity of Müller cells and the underlying mechanism. We studied the effects of PRP-Exos on the fibrogenic activity of human retinal Müller cells (hMCs) in vitro. PRP-Exos were isolated from the plasma of diabetic rats (DM-PRP-Exos) and normal control rats (Nor-PRP-Exos) and then observed by transmission electron microscopy. After treatment with DM-PRP-Exos or Nor-PRP-Exos, the proliferation and migration of hMCs were measured in vitro. Western blotting was conducted to assess the levels of fibrogenic molecules and activation of Yes-associated protein (YAP) and the PI3K-Akt signalling pathway. In cultured hMCs, DM-PRP-Exos but not Nor-PRP-Exos effectively increased the proliferative and migratory activities and improved connective tissue growth factor (CTGF) and fibronectin expression. Genetic and pharmacological suppression of YAP could reduce the proliferative and migratory activities of hMCs induced by DM-PRP-Exo. Additionally, YAP knockdown inhibited the DM-PRP-Exo-induced up-regulation of CTGF and fibronectin. Furthermore, DM-PRP-Exo-induced PI3K-Akt signalling mediated YAP activation and the expression of CTGF and fibronectin. In summary, DM-PRP-Exos, through YAP activation, enhance both the proliferation and fibrogenic activity of Müller cells via the PI3K/Akt pathway.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Retinopatia Diabética/genética , Células Ependimogliais/metabolismo , Exossomos/genética , Regulação da Expressão Gênica , Plasma Rico em Plaquetas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Western Blotting , Células Cultivadas , Diabetes Mellitus Experimental , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Células Ependimogliais/ultraestrutura , Exossomos/metabolismo , Imuno-Histoquímica , Microscopia Eletrônica , Ratos , Ratos Wistar
18.
BMC Pharmacol Toxicol ; 21(1): 9, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019593

RESUMO

BACKGROUND: Cyclosporine-A has been regarded as an immunoregulatory and anti-inflammatory drug for the treatment of various immune inflammatory diseases. However, the effect of Cyclosporine-A on the retina of type 2 diabetic rats and the underlying mechanism remains to be elucidated. The objective of the present study was to investigate the effect and mechanism of Cyclosporine-A on diabetic retinopathy. METHODS: Male Sprague-Dawley rats were established to type 2 diabetic model. After 6 weeks, diabetic rats and normal controls were intravitreally injected with. Cs-A (42 ng/2 µL) to the left eye, and 2 µL DMSO to the right eye for the control.. Another group of normal wild-type rats was subjected to intravitreal injections into. The left eyes with 5 µL PBS or HMGB-1 (5 ng/5 µL) or HMGB-1(5 ng/5 µL) plus. Cs-A (42 ng/2 µL), respectively. Retinal morphological changes were observed with. Hematoxylin-eosin staining. Expressions of HMGB-1, IL-1ß and TNF-α were. Detected by immunohistochemistry, ELISA or Western blot or RT-PCR. RESULTS: Retinal expression levels of IL-1ß and TNF-α were upregulated in type 2. diabetic rats and in normal rats with intravitreal injection of HMGB-1, which were. Attenuated by intravitreal Cs-A. Moreover, Cs-A decreased HMGB-1 expression in. diabetic retina and relieved the retinopathy in type 2 diabetic rats. CONCLUSIONS: Intravitreal administration of Cs-A showed a protective effect on retina. of diabetic rats, possibly by downregulating retinal expressions of IL-1ß and TNF-α. via the suppression of HMGB-1.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ciclosporina/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Proteína HMGB1/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Ciclosporina/farmacologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Proteína HMGB1/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Injeções Intravítreas , Masculino , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
BMC Med Genet ; 21(1): 25, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028915

RESUMO

BACKGROUND: The aim of this study was to explore the association between diabetic retinopathy (DR) and the variants of uncoupling proteins (UCPs) genes in a Chinese population of type 2 diabetes, in total and in patients of different glycemic status separately. METHODS: This case-control study included a total of 3107 participants from two datasets, among which 662 were DR patients (21.31%). Eighteen tag single nucleotide polymorphisms (SNPs) of UCP1, UCP2, and UCP3 were selected as genetic markers. TaqMan probes, Sequenom MassARRAY MALDI-TOF mass spectrometry platform and Affymetrix Genome-Wide Human SNP Array were used for genotyping. Online SHEsis software was used for association analysis. Bonferroni correction was used for multiple comparisons correction. RESULTS: Three SNPs of UCP1: rs7688743 (A allele, OR = 1.192, p = 0.013), rs3811787 (T allele, OR = 0.863, p = 0.023), and rs10011540 (G allele, OR = 1.368, p = 0.004) showed association with DR after the adjustment of glucose, but only rs10011540 was marginally significantly associated with DR when Bonferroni correction was strictly applied (padj = 0.048). In patients with uncontrolled glucose, rs7688743 (A allele, p = 0.012, OR = 1.309), rs10011540 (G allele, p = 0.033, OR = 1.432), and rs3811787 (T allele, p = 0.022, OR = 0.811) were associated with DR, while in participants with well controlled glucose, the rs2734827 of UCP3 was associated with DR (A allele, p = 0.017, OR = 0.532). Rs3811787 of UCP1 showed a protective effect to sight threatening DR (T allele, p = 0.007, OR = 0.490), and the association existed after the adjustment for environmental factors and the correction. In patients with uncontrolled glucose, the rs3811787 of UCP1 (T allele, p = 0.017, OR = 0.467) and the rs591758 of UCP3 (C allele, p = 0.026, OR = 0.103) were associated with STDR. While in those with well controlled glucose, only the rs7688743 of UCP1 showed a protective effect (A allele, p = 0.024, OR = 0.049). None of the associations remain significant when Bonferroni correction was strictly applied (all p < 0.05). CONCLUSIONS: The rs10011540 and rs3811787 of the UCP1 gene was marginally significantly associated with DR in Chinese type 2 diabetes patients. There might be different mechanisms of DR development in patients with different glycemic status.


Assuntos
Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/genética , Predisposição Genética para Doença , Proteína Desacopladora 1/genética , Idoso , Alelos , Retinopatia Diabética/fisiopatologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Desacoplamento Mitocondrial/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína Desacopladora 2/genética , Proteína Desacopladora 3/genética
20.
DNA Cell Biol ; 39(3): 441-450, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32101049

RESUMO

Diabetes mellitus (DM) is one of the growing public health threats globally and as one of the common serious microvascular complications of DM, diabetic retinopathy (DR) is the leading cause of irreversible visual impairments and blindness. There is growing concern about the role of microRNAs (miRNAs) in the pathogenesis of DR. This meta-analysis was designed to collect those published miRNA expression profiling studies that compared the miRNA expression profiles in the biological samples of DR patients with those in the control group. Eight publications were finally included in the meta-analysis, and a total of 93 differentially expressed miRNAs were reported. Although six miRNAs were reported in at least two studies and with the consistent direction, after stratification by the type of biological samples, miR-320a was consistently reported to be upregulated in two serum sample-based studies and miR-423-5p was consistently reported to be upregulated in two vitreous humor sample-based studies. miR-27b was consistently reported to be downregulated in two serum sample-based studies. In conclusion, the results of this meta-analysis of human DR miRNAs' expression profiling studies might provide some clues of the potential biomarkers of DR. Further investigation of the mechanisms of miRNAs and more external validation studies are warranted with the aim of developing new diagnostic markers for preventing or reversing DR.


Assuntos
Retinopatia Diabética/genética , MicroRNAs/genética , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Análise em Microsséries , Pessoa de Meia-Idade , Regulação para Cima , Corpo Vítreo/metabolismo
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