Role of microRNAs in the modulation of diabetic retinopathy

Mastropasqua, Rodolfo; Toto, Lisa; Cipollone, Francesco; Santovito, Donato; Carpineto, Paolo; Mastropasqua, Leonardo

doi:10.1016/j.preteyeres.2014.07.003

Cited by 127 publications

(108 citation statements)

References 152 publications

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“…The in vivo function of miRs in DR and AMD is still largely unknown (14,15). 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).…”

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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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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“…MicroRNAs are a group of small (~22 nucleotide) single-stranded RNA molecules that do not code for protein, but act post-transcriptionally to modulate expression of target genes, including genes involved in the following physiological and disease processes through a mechanism that inhibits protein expression by interfering with mRNA translation and stability [302]:…”

Section: Epigeneticsmentioning

confidence: 99%

“…Recently, three miRNAs in serum of patients with diabetic retinopathy have been reported as potential biomarkers of the disease [4,302,306]. Our team is currently taking a discovery rather than a candidate approach to microRNAs for latestage diabetic retinopathy, and recently published a paper highlighting the impact of the instrumentation used for detection of these molecular biomarkers [85].…”

Section: Epigeneticsmentioning

confidence: 99%

Biomarkers in Diabetic Retinopathy

et al. 2015

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■ AbstractThere is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy.

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“…Experimental models of diabetic retinopathy have shown an association between the downregulation of miR-126, miR-146a and miR-200b and upregulation of VEGF, and downregulation of miR-146a is also associated with fibronectin production, and upregulation of miR-195 with downregulation of deacetylase Sirt1. Upregulation of miR-29b in the early stages of diabetes is considered to be protective against apoptosis of the retinal ganglion cells [83,84]. These studies have clearly suggested the important role for miRNAs in regulating various aspects of diabetic retinopathy, including blood retinal breakdown and neovascularization.…”

Section: Epigenetic Modification and Diabetesmentioning

confidence: 99%

“…Since miRNAs are considered as potential diagnostic biomarkers for disease, double-stranded miRNA mimics and anti-mRNA antisense oligo-deoxyribonucleotide are being used to target specific miRNA [84]. Also, since one miRNA can have a number of targets, a therapy targeting a specific miRNA can also alter other pathways associated with the disease [81,82].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Contribution of epigenetics in diabetic retinopathy

Kowluru

Mishra

2015

Sci. China Life Sci.

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Diabetes has become the epidemic of the 21st century, and with over 90% patients with diabetes becoming at a risk of developing retinopathy, diabetic retinopathy has emerged as a major public health concern. In spite of cutting edge research in the field, how retina and its vasculature are damaged by the diabetic milieu remains ambiguous. The environmental factors, life style or disease process can also bring in modifications in the DNA, and these epigenetic modifications either silence or activate a gene without altering the DNA sequence. Diabetic environment up-or downregulates a number of genes in the retina, and emerging research has shown that it also facilitates epigenetic modifications. In the pathogenesis of diabetic retinopathy, the genes associated with important enzymes (e.g., mitochondrial superoxide dismutase, matrix metalloproteinase-9 and thioredoxin interacting protein) and transcriptional factors are epigenetically modified, the enzymes responsible for these epigenetic modifications are either activated or inhibited, and the levels of microRNAs are altered. With epigenetic modifications taking an important place in diabetic retinopathy, it is now becoming critical to evaluate these modifications, and understand their impact on this slow progressing blinding disease. diabetic retinopathy, epigenetic modifications, histone acetylation, histone methylation, miRNA Citation:Kowluru RA, Mishra M. Contribution of epigenetics in diabetic retinopathy.

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Role of microRNAs in the modulation of diabetic retinopathy

Cited by 127 publications

References 152 publications

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

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

Biomarkers in Diabetic Retinopathy

Contribution of epigenetics in diabetic retinopathy

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