Anti-VEGF effects of intravitreal erythropoietin in early diabetic retinopathy.
In the present study, a single intravitreal erythropoietin (EPO) to diabetic rats produced therapeutic effects on blood-retinal barrier (BRB) function and neuronal survival at different time courses of retinopathy. In parallel, the hypoxia-inducible factor 1 alpha (HIF-1 alpha) pathway has been quantitatively studied, including VEGF-A, endogenous EPO, EPO receptor (EpoR), prolyl hydroxylases (PHD1-3) and von Hippel-Lindau tumor suppressor (VHL). The mRNA levels of HIF-1 alpha, VEGF-A, endogenous EPO, PHD1-3 and VHL are 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 also have been 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 exerted neuronal protection.
Zhang
Jingfa
J
Department of Regenerative Medicine, Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.
Hu
Liu-Mei
LM
Xu
Guoxu
G
Wu
Yalan
Y
Shen
Jianfeng
J
Luo
Yan
Y
Zhong
Yong
Y
Sinclair
Stephen H
SH
Yanoff
Myron
M
Li
Weiye
W
Xu
Guo-Tong
GT
D000818:Animals; D001483:Base Sequence; D001813:Blood-Retinal Barrier; D017931:DNA Primers; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D004921:Erythropoietin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020287:In Situ Nick-End Labeling; D008297:Male; D008854:Microscopy, Electron; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014822:Vitreous Body
D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin