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G.-T. Xu, J. Zhang, L.-M. Hu, W. Li, W. Li; Anti-VEGF Effects Through Negative Feedback Regulation With Intravitreal Injection of Erythropoietin in Early Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):36.
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Since intravitreal erythropoietin (EPO) is able to restore blood-retinal barrier of diabetic rats (Invest Ophthalmol Vis Sci 2008;49:732-742), the inhibitory mechanism of EPO on VEGF is explored.
A single intravitreal injection of EPO was given to streptozotocin-induced diabetic rats at 2, 4 weeks and 5 months after diabetes onset. BRB permeability was studied, along with the detection of hypoxia-inducible factor 1 (HIF-1) pathway, including vascular endothelial growth factor A (VEGF-A), endogenous EPO, EPO receptor (EpoR), prolyl hydroxylases (PHD1-3) and von Hippel-Lindau tumor suppressor (VHL) by real-time PCR and Western blot.
EPO administered after diabetic onset effectively maintained BRB function. The mRNA levels of HIF-1, VEGF-A, endogenous EPO, PHD1-3 and VHL were all up-regulated in the diabetic retina, and suppressed by exogenous EPO. The increased protein levels of HIF-1, VEGF-A, and endogenous EPO in diabetic retinas were also significantly down-regulated by exogenous EPO. A generalized decrease in VEGF distribution throughout the EPO-treated diabetic retina was demonstrated by immunofluorescence.
Activation of the HIF-1 pathway was observed in early diabetic retina. The regulation of HIF-1 pathway by exogenous EPO was documented at both transcriptional and translational levels. This down-regulation of HIF-1 pathway was presumably achieved by a negative feedback mechanism at therapeutic levels of EPO. EPO appears to lead to suppression of VEGF and in turn, restoration of the normal functions of BRB.
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