Abstract
The dysregulated microRNAs (miRNAs) are involved in diabetic retinopathy progression. Epithelial mesenchymal transition (EMT) and cell permeability are important events in diabetic retinopathy. However, the function and mechanism of miR-195 in EMT and cell permeability in diabetic retinopathy remain largely unclear. Diabetic retinopathy models were established using streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-stimulated ARPE-19 cells. Retina injury was investigated by hematoxylin–eosin (HE) staining. EMT and cell permeability were analyzed by western blotting, immunofluorescence, wound healing, and FITC-dextran assays. MiR-195 expression was detected via qRT-PCR. YY1, VEGFA, Snail1, and Smurf2 levels were detected via western blotting. The interaction relationship was analyzed via ChIP, Co-IP, or dual-luciferase reporter assay. The retina injury, EMT, and cell permeability were induced in STZ-induced diabetic mice. HG induced EMT and cell permeability in ARPE-19 cells. MiR-195, YY1, VEGFA, and Snail1 levels were enhanced, but Smurf2 abundance was reduced in STZ-induced diabetic mice and HG-stimulated ARPE-19 cells. VEGFA knockdown decreased Snail1 expression and attenuated HG-induced EMT and cell permeability. YY1 silence reduced VEGFA and Snail1 expression, and mitigated HG-induced EMT and cell permeability. YY1 could bind with VEGFA and Snail1, and it was degraded via Smurf2-mediated ubiquitination. MiR-195 knockdown upregulated Smurf2 to decrease YY1 expression and inhibited HG-induced EMT and cell permeability. MiR-195 targeted Smurf2, increased expression of YY1, VEGFA, and Snail1, and promoted HG-induced EMT and cell permeability. MiR-195 promotes EMT and cell permeability of HG-stimulated ARPE-19 cells by increasing VEGFA/Snail1 via inhibiting the Smurf2-mediated ubiquitination of YY1.
Highlights
Diabetic retinopathy is a common clinical disease occurring in ~35% diabetic patients, with hyperglycemia as a main risk, which can induce blindness or severe vision impairment [1]
We mainly aimed to investigate the function of Vascular endothelial growth factor A (VEGFA)/Snail1 axis, Yin Yang 1 (YY1), and miR-195 on Epithelial mesenchymal transition (EMT) and permeability of retinal pigment epithelial cells under high glucose (HG) condition, and to confirm the mechanism was associated with the miR
MiR-195, YY1, VEGFA, and Snail1 levels are increased, whereas Smad ubiquitin regulatory factor 2 (Smurf2) expression is decreased in STZ-induced diabetic mice and HG-stimulated Adult Retinal Pigment Epithelial cell line-19 (ARPE-19) cells To explore whether miR-195, YY1, VEGFA, Snail1, and Smurf2 were involved in diabetic retinopathy progression, their expression levels were detected in STZ-induced diabetic mice and HG-stimulated ARPE-19 cells
Summary
Diabetic retinopathy is a common clinical disease occurring in ~35% diabetic patients, with hyperglycemia as a main risk, which can induce blindness or severe vision impairment [1]. The permeability by disturbing the blood-retinal barrier cell junctions is an important feature in diabetic retinopathy [4]. Exploring the mechanism of EMT and permeability of retinal pigment epithelial cells may contribute to find a promising strategy for diabetic retinopathy therapy. Snail is an important transcriptional suppressor of E-cadherin, which contributes to EMT in retinal pigment epithelium cells [6, 7]. Vascular endothelial growth factor A (VEGFA) is a key factor promoting retinal vascular permeability in retinal vascular diseases [9] and the VEGFA/VEGFR2 signaling is associated with HG-induced EMT and permeability of retinal pigment epithelial cells [10]. Whether YY1 can target VEGFA/Snail axis to participate in EMT and permeability of retinal pigment epithelial cells is unknown
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