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Jiawen Fan, Gezhi Xu, Tingting Jiang, Yaowu Qin, Xin Wang; MicroRNA-126 Regulates Heme Oxygenase-1-Mediated Alterations in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6199.
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Diabetic retinopathy (DR) is a progressive neurodegenerative disease and a leading cause of blindness. Overexpression of Heme Oxygenase-1(HO-1) by hemin induction protected retinal ganglion cells in diabetic retinopathy through anti-inflammatory, anti-apoptotic, and anti-proliferative effects. We investigated microRNA (miRNA) alterations in DR after hemin treatment with specific focus on miR-126, and its downstream target, HO-1.
miRNA expression profiling microarray (Affymetrix MicroRNA 2.0 Array) was used to examine the retinas of treated and non-treated streptozotocin- induced diabetic rats. Expressions of specific miRNAs were verified with PCR in the rat retina and in glucose-exposed endothelial cells. A target search, based on sequence complementarities, identified specific targets. We analyzed mRNA levels and protein expression in endothelial cells from large vessels and retinal capillaries and in the rat retina, with or without injection of miR-126 mimic or antagomir. Localization of miR-126 and its functional analysis in the rat retinas and vascular endothelial cells were performed.
Significant alteration of several miRNAs, including downregulation of miR-126, were observed in the retina in non-treated diabetes. Such downregulation was validated in vascular endothelial cells incubated in glucose. In parallel, HO-1 (target of miR-126) mRNA and protein were degraded. The level of both miR-126 and HO-1were elevated after hemin treatment in diacetic rats’ retina and vascular endothelial cells with high glucose. In the retina, miR-126 was localized in glial and vascular elements. Transfection of endothelial cells and intravitreal injection of miR-126 mimic prevented diabetes-induced decreased HO-1 and increased VEGF mRNA and protein. Also prevented were glucose-induced increased permeability and angiogenesis. Furthermore, transfection of miR-126 antagonists (antagomir) led to decreased HO-1 and increased VEGF production.
These studies show a novel mechanism involving miR-126 in DR. Identification of such mechanisms may lead to the development of novel miRNA-based therapy.
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