Abstract
Hypoxia is the most important factor in the pathogenesis of diabetic retinopathy (DR). Our previous studies demonstrated that G protein-coupled receptor 91(GPR91) participated in the regulation of vascular endothelial growth factor (VEGF) secretion in DR. The present study induced OIR model in newborn rats using exposure to alternating 24-hour episodes of 50% and 12% oxygen for 14 days. Treatment with GPR91 shRNA attenuated the retinal avascular area, abnormal neovascularization and pericyte loss. Western blot and qRT-PCR demonstrated that CoCl2 exposure promoted VEGF expression and secretion, activated the ERK1/2 signaling pathways and upregulated C/EBP and AP-1. Knockdown of GPR91 inhibited ERK1/2 activity. GPR91 siRNA transduction and the ERK1/2 inhibitor U0126 inhibited the increases in C/EBP β, C/EBP δ, c-Fos and HIF-1α. Luciferase reporter assays and a chromatin immunoprecipitation (ChIP) assay demonstrated that C/EBP β and c-Fos bound the functional transcriptional factor binding site in the region of the VEGF promoter, but not C/EBP δ. Knockdown of C/EBP β and c-Fos using RNAi reduced VEGF expression. Our data suggest that activation of the GPR91-ERK1/2-C/EBP β (c-Fos, HIF-1α) signaling pathway plays a tonic role in regulating VEGF transcription in rat retinal ganglion cells.
Highlights
Vascular endothelial growth factor (VEGF) is a prominent angiogenic factor that drives the proliferation and migration of vascular endothelial cells and induces vascular permeability[1,2]
We investigated the role of GPR91 in the regulation of vascular endothelial growth factor (VEGF) expression in the retinas of oxygen-induced retinopathy (OIR) rats
Our previous research demonstrated that succinate were increased in the retina of streptozotocin-induced diabetic rats, and succinate regulated VEGF expression via activation and binding to its special receptor in the ganglion neural cells (GCL)[7]
Summary
Vascular endothelial growth factor (VEGF) is a prominent angiogenic factor that drives the proliferation and migration of vascular endothelial cells and induces vascular permeability[1,2]. Sapieha et al.[4] presented a strong correlation between G protein-coupled receptor 91(GPR91) and VEGF in hypoxia-induced retinopathy. GPR91 is activated by specific binding with extracellular succinate, and it is associated with neovascularization[4,6]. Understanding the mechanisms of VEGF transcriptional regulation is of paramount importance to expand our knowledge of GPR91-dependent VEGF expression and enhance the sensitivity and specificity of genome-wide efforts to characterize it. Belonging to the rat source yielded two transcription factors: CCAAT enhancer binding protein (C/EBP) and activator protein-1 (AP-1), with scores of 93.1 and 90.7, respectively. Extracellular regulated protein kinases 1/2 (ERK1/2) is the upstream signal that enhances the binding of C/EBPβto the promoter region of VEGF-C16
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