Carbamylated erythropoietin mediates retinal neuroprotection in streptozotocin-induced early-stage diabetic rats.
OBJECTIVE
The neuroprotective effect of carbamylated erythropoietin (CEPO), an erythropoietin (EPO) derivative, in diabetic retinopathy (DR) has not been clearly verified. We conducted this study to investigate the potential neuroprotective role of CEPO in a streptozotocin-induced diabetic rat model.


METHODS
Streptozotocin-induced diabetic rats and blank controls were treated with or without CEPO and EPO for 4 weeks. Retinal functional and histological changes were quantified by electroretinogram, light microscopy, and terminal dUTP nick end labeling assay. Gene and protein levels of colony-stimulating factor 2 receptor beta, low-affinity (CD131), EPO receptor (EPOR), THY1, glial fibrillary acidic protein (GFAP), and vascular endothelial growth factor (VEGF-A) in retinal tissues were determined by real-time PCR and western blotting, respectively. Vascular penetration was assessed by fluorescein retinal angiography.


RESULTS
Diabetic rats had decreased retinal thickness, decreased ganglion cells, and increased retinal neuron apoptosis. CEPO increased CD131 and THY1 expression, while EPO increased EPOR expression. High glucose increased GFAP expression in the diabetic group, but both CEPO and EPO attenuated the trend for increase. CEPO downregulated VEGF-A expression. The amplitudes of b-wave and oscillatory potentials were decreased in the untreated diabetic group, whereas neither parameter decreased in diabetic rats after CEPO or EPO treatment. Vascular leakage and microaneurysms in the diabetic group were significantly improved following CEPO treatment.


CONCLUSIONS
CEPO has similar anti-apoptotic effects to EPO in DR, but CEPO does not induce neovascularization. CEPO may exert neuroprotective effects via its receptor CD131.
Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Xiaojing
X
Liu
Bijun
B
Zhu
Haidong
H
Zou
Daode
D
Hu
Qing
Q
Gu
Kun
K
Liu
Xun
X
Xu
D000818:Animals; D015153:Blotting, Western; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004596:Electroretinography; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005451:Fluorescein Angiography; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D017467:Receptors, Erythropoietin / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000502:physiology; D013311:Streptozocin; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D053648:Cytokine Receptor Common beta Subunit; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D017467:Receptors, Erythropoietin; D042461:Vascular Endothelial Growth Factor A; C488171:carbamylated erythropoietin; C467498:vascular endothelial growth factor A, rat; D004921:Erythropoietin; D013311:Streptozocin