Up-regulated Endogenous Erythropoietin/Erythropoietin Receptor System and Exogenous Erythropoietin Rescue Retinal Ganglion Cells after Chronic Ocular Hypertension
- 299 Downloads
Recent studies have showed that erythropoietin (EPO) is a neuroprotectant for central nerve system neurons in addition to being a hematopoietic cytokine in response to hypoxia. In this study, we investigate the role of the EPO/EPO receptor (EPOR) system in the rat retina after ocular hypertension injury that mimics glaucoma.
Elevated intraocular pressure was induced by laser coagulation of the episcleral and limbal veins. Expression of EPO and EPOR in the normal and glaucomous retinas was investigated by immunohistochemistry and Western blot. To examine the effects of endogenous EPO on the survival of retinal ganglion cells (RGCs) subjected to hypertensive injury, soluble EPOR was directly injected into the vitreous body. Recombinant human EPO was both intravitreally and systemically administrated to study the effect of exogenous EPO on the survival of RGCs after ocular hypertension injury.
Immunohistochemistry studies identified Müller cells as the main source of EPO in the normal retina. Expression of EPO and EPOR proteins was increased significantly 2 weeks after ocular hypertension. RGCs, amacrine and bipolar cells all demonstrated an increased expression of EPOR after ocular hypertension. Neutralization of endogenous EPO with soluble EPOR exacerbated ocular hypertensive injury, suggesting a role of the EPO/EPOR system in the survival of RGCs after injury. Similarly, topical and systemic administration of recombinant human EPO rescues RGCs after chronic ocular hypertension.
These results indicate that an endogenous EPO/EPOR system participates in intrinsic recovery mechanisms after retina injury and RGCs might be rescued by exogenous administration of EPO.
KeywordsErythropoietin Erythropoietin receptor Retinal ganglion cell Glaucoma Intraocular pressure Endogenous Neuroprotectant
We gratefully acknowledge Dr. Daniel HS Lee from Biogen Idec, Inc. USA for his valuable comments. This research is supported by a donation from the Hong Kong Eye Charitable Foundation, and Ms. Annie Tso Wen Wei.
- Buemi M, Cavallaro E, Floccari F, Sturiale A, Aloisi C, Trimarchi M, Grasso G, Corica F, Frisina N (2002) Erythropoietin and the brain: from neurodevelopment to neuroprotection. Clin Sci (Lond) 103:275–282Google Scholar
- Gorio A, Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Vardar E, Cerami A, Brines M (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci USA 99:9450–9455PubMedCrossRefGoogle Scholar
- Grasso G, Sfacteria A, Erbayraktar S, Passalacqua M, Meli F, Gokmen N, Yilmaz O, La TD, Buemi M, Iacopino DG, Coleman T, Cerami A, Brines M, Tomasello F (2006) Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative. J Neurosurg Spine 4:310–318PubMedCrossRefGoogle Scholar
- Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 98:4044–4049PubMedCrossRefGoogle Scholar