Abstract
Diabetic retinopathy (DR) is the leading cause of blindness among American adults above 40 years old. The vascular complication in DR is a major cause of visual impairment, making finding therapeutic targets to block pathological angiogenesis a primary goal for developing DR treatments. MicroRNAs (miRs) have been proposed as diagnostic biomarkers and potential therapeutic targets for various ocular diseases including DR. In diabetic animals, the expression levels of several miRs, including miR-150, are altered. The expression of miR-150 is significantly suppressed in pathological neovascularization in mice with hyperoxia-induced retinopathy. The purpose of this study was to investigate the functional role of miR-150 in the development of retinal microvasculature complications in high-fat-diet (HFD) induced type 2 diabetic mice. Wild type (WT) and miR-150 null mutant (miR-150-/-) male mice were given a HFD (59% fat calories) or normal chow diet. Chronic HFD caused a decrease of serum miR-150 in WT mice. Mice on HFD for 7 months (both WT and miR-150-/-) had significant decreases in retinal light responses measured by electroretinograms (ERGs). The retinal neovascularization in miR-150-/--HFD mice was significantly higher compared to their age matched WT-HFD mice, which indicates that miR-150 null mutation exacerbates chronic HFD-induced neovascularization in the retina. Overexpression of miR-150 in cultured endothelial cells caused a significant reduction of vascular endothelial growth factor receptor 2 (VEGFR2) protein levels. Hence, deletion of miR-150 significantly increased the retinal pathological angiogenesis in HFD induced type 2 diabetic mice, which was in part through VEGFR2.
Highlights
Obesity associated type 2 diabetes has reached epidemic proportions in the past few decades
Unlike other diabetic mouse models derived from monogenic disorders or chemical destruction of β-cells, the HFD-induced diabetic mouse model is widely used in studies on pathophysiology of obesity and type 2 diabetes, such as mechanisms of impaired glucose tolerance and insulin resistance, as well as other diabetic complications [35,43], and it is more clinically relevant to obesity-associated type 2 diabetes in humans [35,43]
While overexpression of miR-150 in the mouse retina is able to block neovascularization in hyperoxia-induced retinopathy mice [33], it is unclear how miR-150 might affect retinal function under diabetic conditions. We examined both neuronal and vascular changes in the retina of age matched wild type (WT) and miR-150-/- mice fed with a HFD for 27 weeks to determine the functional role of miR-150 in Diabetic retinopathy (DR) pathogenesis
Summary
Unlike other diabetic mouse models derived from monogenic disorders or chemical destruction of β-cells, the HFD-induced diabetic mouse model is widely used in studies on pathophysiology of obesity and type 2 diabetes, such as mechanisms of impaired glucose tolerance and insulin resistance, as well as other diabetic complications [35,43], and it is more clinically relevant to obesity-associated type 2 diabetes in humans [35,43] These HFD-induced diabetic mice have structural and functional deficits in the retina similar to certain characteristics found in other DR animal models, including defects in the inner retinal light responses, lesions in the retinal vasculature, and thickness of Bruch's membrane [44]. We further examined the HFD-induced DR in miR-150 null mutant (miR-150-/-) mice and determined the functional role of miR-150 in neovascularization under diabetic conditions, as well as the downstream target(s) of miR-150 by using ERG recordings for retinal light responses, morphological staining for retinal vasculature, and other biochemical / molecular assays
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