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J. Zhang, L.-M. Hu, G. Xu, Y. Wu, J. Shen, Y. Luo, Y. Zhong, S. H. Sinclair, W. Li, G.-T. Xu; Anti-VEGF Effects of Intravitreal Erythropoietin in Early Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5601.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the underlying mechanisms of the therapeutic effects of intravitreal erythropoietin (EPO) for early diabetic retinopathy (DR).
A single intravitreal injection of EPO (8-160 mU/eye) was given to streptozotocin-induced diabetic rats at different time points during the course of diabetes. Blood-retinal barrier (BRB) permeability, neuronal apoptosis and retinal morphology were studied. In parallel, the key factors of hypoxia-inducible factor 1 alpha (HIF-1 alpha) pathway have been quantitatively studied, including VEGF-A, endogenous EPO, EPO receptor (EpoR), prolyl hydroxylases (PHD1-3) and von Hippel-Lindau tumor suppressor (VHL).
In the present study, a single intravitreal erythropoietin (EPO) to diabetic rats produced therapeutic effects on maintaining blood-retinal barrier (BRB) function and neuronal survival at different time courses of retinopathy. The mRNA levels of HIF-1 alpha, 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 alpha, VEGF-A, and endogenous EPO found in diabetic retinas were also down-regulated by exogenous EPO.
The results demonstrate that the HIF-1 pathway is activated in the retina in early diabetes, but is negatively regulated by a feedback loop following the administration of exogenous EPO. Exogenous EPO at pharmacologic levels leads to suppression of VEGF and in turn, restoration of the normal functions of BRB in a time-dependent manner. In the diabetic retina, the same level of exogenous EPO that inhibits VEGF also exerts neuronal protection.
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