microRNAs in Early Diabetic Retinopathy in Streptozotocin-Induced Diabetic Rats

Kovacs, Beatrix; Lumayag, Stephen; Cowan, Colleen; Xu, Shunbin

doi:10.1167/iovs.10-6879

Cited by 246 publications

(272 citation statements)

References 52 publications

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“…In the present study, Produced as small, non-protein-coding RNAs, miRNAs are endogenous regulators that play significant roles in many cellular processes [33,34]. Accumulating evidence has recently illustrated the role of miRNAs in the pathogenesis of diabetes and its complications, including diabetic retinopathy [15,35,36]. The miRNA miR-125b plays a role in the dysregulation of Suv39h1 and associated chromatin H3K9me3 related to the increased expression of inflammatory genes in the vascular smooth muscle cells of diabetic mice.…”

Section: Discussionmentioning

confidence: 70%

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

Zhao

et al. 2015

Diabetologia

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Aims/hypothesis The mechanisms underlying the cellular metabolic memory induced by high glucose remain unclear. Here, we sought to determine the effects of microRNAs (miRNAs) on metabolic memory in diabetic retinopathy. Methods The miRNA microarray was used to examine human retinal endothelial cells (HRECs) following exposure to normal glucose (N) or high glucose (H) for 1 week or transient H for 2 days followed by N for another 5 days (H→N). Levels of sirtuin 1 (SIRT1) and acetylated-nuclear factor κB (Ac-NF-κB) were examined following transfection with miR-23b-3p inhibitor or with SIRT1 small interfering (si)RNA in the H→N group, and the apoptotic HRECs were determined by flow cytometry. Retinal tissues from diabetic rats were similarly studied following intravitreal injection of miR-23b-3p inhibitor. Chromatin immunoprecipitation (ChIP) analysis was performed to detect binding of NF-κB p65 to the potential binding site of the miR-23b-27b-24-1 gene promoter in HRECs. Results High glucose increased miR-23b-3p expression, even after the return to normal glucose. Luciferase assays identified SIRT1 as a target mRNA of miR-23b-3p. Reduced miR-23b-3p expression inhibited Ac-NF-κB expression by rescuing SIRT1 expression and also relieved the effect of metabolic memory induced by high glucose in HRECs. The results were confirmed in the retina using a diabetic rat model of metabolic memory. High glucose facilitated the recruitment of NF-κB p65 and promoted transcription of the miR-23b-27b-24-1 gene, which can be suppressed by decreasing miR-23b-3p expression. Conclusions/interpretation These studies identify a novel mechanism whereby miR-23b-3p regulates high-glucoseinduced cellular metabolic memory in diabetic retinopathy through a SIRT1-dependent signalling pathway.

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Section: Discussionmentioning

confidence: 70%

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

Zhao

et al. 2015

Diabetologia

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“…These disorders include primary vitreo‐retinal lymphoma, uveitis, ocular adnexal lymphoma or diabetic retinopathy among other conditions (Kovacs et al. 2011; Dunmire et al. 2013; Funari et al.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA regulation in an animal model of acute ocular hypertension

Wang

Valiente‐Soriano

Nadal-Nicolás

et al. 2016

Acta Ophthalmologica

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PurposeTo analyse miRNA regulation in a rat model of acute ocular hypertension (AOH).MethodsAcute ocular hypertension (AOH) was induced in the left eye of adult albino rats by inserting a cannula connected with a saline container into the anterior chamber. The contralateral eye served as a control. Seven days later, animals were killed. Retinas were used either for quantitative analysis of retinal ganglion cells (RGCs) and microglial cells or for miRNA array hybridization, qRT‐PCR and Western blotting.ResultsAnatomically, AOH caused axonal degeneration, a significant loss of RGCs and a significant increase in microglial cells in the ganglion cell layer. The miRNAs microarray analysis revealed 31 differentially expressed miRNAs in the AOH versus control group, and the regulation of 12 selected microRNAs was further confirmed by qRT‐PCR. Bioinformatic analysis indicates that several signalling pathways are putatively regulated by the validated miRNAs. Of particular interest was the inflammatory pathway signalled by mitogen‐activated protein kinases (MAPKs). In agreement with the in silico analysis, p38 MAP kinase, tumour necrosis factor‐alpha (TNF‐α) and iNOS proteins were significantly upregulated in the AOH retinas.ConclusionsAcute IOP elevation led to changes in the expression of miRNAs, whose target genes were associated with the regulation of microglia‐mediated neuroinflammation or neural apoptosis. Addressing miRNAs in the process of retinal ischaemia and optic nerve damage in association with high IOP elevation may open new avenues in preventing retinal ganglion cell apoptosis and may serve as target for future therapeutic regimen in acute ocular hypertension and retinal ischaemic conditions.

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“…Several miRs, including let-7, miR-375, miR-9, miR-103/107, miR-143/145, and miR-144, have been shown to regulate insulin production, release, or insulin sensitivity (16)(17)(18)(19)(20)(21)(22). A number of miRs have been shown to be significantly regulated in the retinas or retinal ECs (RECs) in streptozotocin-induced or Akita (type I diabetic) DR animal models or in the oxygen-induced retinopathy model (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Particularly, miR-146a and miR-146b are upregulated in the RECs of diabetic rats and act as negative feedback on NF-B activation to control the inflammatory response (23,33); miR-200b and miR-126 are downregulated in a DR mouse model and regulate VEGF expression during retinal neovascularization (25,29); miR-200b downregulation was also found in the retinas of patients with diabetes (25,34).…”

mentioning

confidence: 99%

“…A number of miRs have been shown to be significantly regulated in the retinas or retinal ECs (RECs) in streptozotocin-induced or Akita (type I diabetic) DR animal models or in the oxygen-induced retinopathy model (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Particularly, miR-146a and miR-146b are upregulated in the RECs of diabetic rats and act as negative feedback on NF-B activation to control the inflammatory response (23,33); miR-200b and miR-126 are downregulated in a DR mouse model and regulate VEGF expression during retinal neovascularization (25,29); miR-200b downregulation was also found in the retinas of patients with diabetes (25,34). However, miR-200b was also shown to be significantly upregulated in the retinas of Akita rats and could contribute to increased cell death in DR (26).…”

mentioning

confidence: 99%

let-7 Contributes to Diabetic Retinopathy but Represses Pathological Ocular Angiogenesis

Zhou

Frost

Anderson

et al. 2017

Molecular and Cellular Biology

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The in vivo function of microRNAs (miRs) in diabetic retinopathy (DR) and age-related macular degeneration (AMD) remains unclear. We report here that let-7 family members are expressed in retinal and choroidal endothelial cells (ECs). In ECs, overexpression of let-7 by adenovirus represses EC proliferation, migration, and networking in vitro, whereas inhibition of the let-7 family with a locked nucleic acid (LNA)-anti-miR has the opposite effect. Mechanistically, silencing of the let-7 target HMGA2 gene mimics the phenotype of let-7 overexpression in ECs. let-7 transgenic (let-7-Tg) mice show features of nonproliferative DR, including tortuous retinal vessels and defective pericyte coverage. However, these mice develop significantly less choroidal neovascularization (CNV) compared to wild-type controls after laser injury. Consistently, silencing of let-7 in the eye increased laser-induced CNV in wild-type mice. Together, our data establish a causative role of let-7 in nonproliferative diabetic retinopathy and a repressive function of let-7 in pathological angiogenesis, suggesting distinct implications of let-7 in the pathogenesis of DR and AMD.KEYWORDS let-7, endothelial cells, angiogenesis, diabetic retinopathy, choroidal, neovascularization, AMD T he retina has been an excellent model for studying the mechanism of angiogenesis. Retinal vascularization in mice begins after birth, when endothelial cells (ECs) sprout from the central retinal artery to the peripheral region and then to the intermediate and deep retinal layers (1, 2). Pathological angiogenesis in the eye is the most common cause of blindness at all ages and underlies conditions such as retinopathy of prematurity in children, diabetic retinopathy (DR) in young adults, and age-related macular degeneration (AMD) in the elderly. DR is the leading cause of blindness in working-age adults (18 to 64 years old), with a prevalence of 5.4% (ϳ7.7 million people) in the United States (3). Early-stage DR (or nonproliferative DR [NPDR]) is characterized by pericyte loss, basement membrane thickening, and EC dysfunction. Proliferative diabetic retinopathy (PDR) develops at the advanced stage and is associated with new blood vessel growth along the retina and the vitreous surface. AMD is a degenerative disease of the retina and the leading cause of blindness among the elderly (4). Neovascular (or wet) AMD, which accounts for the majority of acute vision loss in AMD, is characterized by choroidal neovascularization (CNV), a process involving abnormal growth of blood vessels from the choroid into the retina. Vascular endothelial growth factor (VEGF) is a major cytokine driving neovascularization and vascular permeability during CNV and diabetic edema. Several U.S. Food and Drug Administration-approved anti-VEGF agents are the current mainstay for wet AMD treatment and have been recently approved for

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microRNAs in Early Diabetic Retinopathy in Streptozotocin-Induced Diabetic Rats

Abstract: miRNAs are involved in the pathogenesis of DR through the modulation of multiple pathogenetic pathways and may be novel therapeutic targets for the treatment of DR.

Cited by 246 publications

References 52 publications

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

MicroRNA regulation in an animal model of acute ocular hypertension

let-7 Contributes to Diabetic Retinopathy but Represses Pathological Ocular Angiogenesis

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