title: Systemic administration of erythropoietin inhibits retinopathy in RCS rats.
abstract: OBJECTIVE
  Royal College of Surgeons (RCS) rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO) on retinopathy in RCS rats.
  
  
  METHODS
  Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg) was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR), pro-neurotrophin 3 (pro-NT3), tumour necrosis factor-α (TNFα), pigment epithelium derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A), the production of CD34(+) cells and mobilization of CD34(+)/VEGF-R2(+) cells as well as recruitment of CD34(+) cells into the retina were examined after EPO treatment.
  
  
  RESULTS
  RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34(+) cells along with effective mobilization of CD34(+)/VEGF-R2(+) cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina.
  
  
  CONCLUSIONS
  Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple mechanisms including regulation of retinal glia and microglia, inhibition of p75NTR-pro-NT3 signaling together with stimulation of production and mobilization of bone marrow derived cells.
authors.affiliation: Save Sight Institute, the University of Sydney, Sydney, Australia.
authors.forename: Weiyong
authors.initials: W
authors.lastname: Shen
authors.affiliation: Save Sight Institute, the University of Sydney, Sydney, Australia.
authors.forename: Sook H
authors.initials: SH
authors.lastname: Chung
authors.affiliation: Save Sight Institute, the University of Sydney, Sydney, Australia.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Irhimeh
authors.affiliation: Save Sight Institute, the University of Sydney, Sydney, Australia; Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Shiying
authors.initials: S
authors.lastname: Li
authors.affiliation: Save Sight Institute, the University of Sydney, Sydney, Australia.
authors.forename: So-Ra
authors.initials: SR
authors.lastname: Lee
authors.affiliation: Save Sight Institute, the University of Sydney, Sydney, Australia.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Gillies
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003930:Diabetic Retinopathy / Q000517:prevention & control*; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D005434:Flow Cytometry; D005451:Fluorescein Angiography; D005455:Fluorescent Antibody Technique; D007091:Image Processing, Computer-Assisted; D020287:In Situ Nick-End Labeling; D009457:Neuroglia / Q000187:drug effects; D051381:Rats; D011922:Rats, Mutant Strains; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000187:drug effects; D012171:Retinal Vessels / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020800:Receptor, Nerve Growth Factor; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin