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Abstract
Vascular endothelial growth factor-A (VEGF-A) has a pathologic role in microvascular diabetic complication, such as diabetic retinopathy (DR). miR-126 plays an important role in vascular development and angiogenesis by regulating the expression of VEGF-A. Since levels of miR-126 have been found downregulated in diabetes, this study is aimed at investigating whether hyperglycemia affects expression of miR-126 in a retinal pigment epithelium cell line. ARPE-19 cells were transfected with miR-126 inhibitor or with miR-126 mimic and the respective scramble negative control. After 24 hours, medium was replaced and cells were cultured for 24 hours in normal (CTR) or diabetic condition (HG). Then, we analyzed mRNA levels of miR-126, VEGF-A, PI3KR2, and SPRED1. We also evaluated protein amount of HIF-1α, PI3KR2, and SPRED1 and VEGF-A secretion. The results showed that exposure of ARPE-19 cells to HG significantly decreased miR-126 levels; mRNA levels of VEGF-A and PI3KR2 were inversely correlated with those of miR-126. Overexpression of miR-126 under HG restored HIF-1α expression and VEGF-A secretion to the level of CTR cells. These results indicate that reduced levels of miR-126 may contribute to DR progression by increasing expression of VEGF-A in RPE cells. In addition, we provide evidence that upregulation of miR-126 in RPE cells counteracts the rise of VEGF-A secretion induced by hyperglycemia. In conclusion, our data support a role of miR-126 mimic-approach in counteracting proangiogenic effects of hyperglycemia.
Highlights
Diabetic retinopathy (DR) is one of the most important microvascular complications of diabetes and the primary cause of visual loss in working age adults [1,2,3]
Since the retinal pigment epithelium (RPE) cell dysfunction is involved in the early stages of the DR damage and miR-126 represents a promising target for novel antiangiogenic therapies, this study is aimed at investigating whether hyperglycemia affects expression of miR126 and characterizing the molecular mechanisms through which miR-126 regulates Vascular endothelial growth factor-A (VEGF-A) expression in RPE cells
It is well known that the expression of VEGF-A is regulated by the activity of HIF1α, which is stabilized under hypoxia and diabetes [9, 13]
Summary
Diabetic retinopathy (DR) is one of the most important microvascular complications of diabetes and the primary cause of visual loss in working age adults [1,2,3]. Prolonged hyperglycemia is a significant risk factor in the DR progression and could cause ocular neovascularization with aberrant formation of immature blood vessels [4, 5]. It leads to progressive alterations of the retinal microvasculature, which start with pericyte dropout, pass through vasoregression and increased vasopermeability, and lead to pathological neovascularization in response to hypoxia [6]. Vascular endothelial growth factor-A (VEGF-A), a key mediator of blood vessel formation, plays an important role in the homeostasis of the retinal and choroidal vasculature, by mediating both angiogenesis and inflammation [7]. VEGF-A activates quiescent endothelial cells, promotes cell proliferation and migration with the subsequent formation of new blood vessels, and increases vascular permeability [10]
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