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Up-regulated Endogenous Erythropoietin/Erythropoietin Receptor System and Exogenous Erythropoietin Rescue Retinal Ganglion Cells after Chronic Ocular Hypertension

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Abstract

Aims

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.

Methods

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.

Results

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.

Conclusions

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.

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References

  • Becerra SP, Amaral J (2002) Erythropoietin – an endogenous retinal survival factor. N Engl J Med 347:1968–1970

    Article  PubMed  CAS  Google Scholar 

  • Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19:643–651

    Article  PubMed  CAS  Google Scholar 

  • Bocker-Meffert S, Rosenstiel P, Rohl C, Warneke N, Held-Feindt J, Sievers J, Lucius R (2002) Erythropoietin and VEGF promote neural outgrowth from retinal explants in postnatal rats. Invest Ophthalmol Vis Sci 43:2021–2026

    PubMed  Google Scholar 

  • Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A (2000) Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 97:10526–10531

    Article  PubMed  CAS  Google Scholar 

  • 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) 103:275–282

    CAS  Google Scholar 

  • Cheung ZH, Chan YM, Siu FK, Yip HK, Wu W, Leung MC, So KF (2004) Regulation of caspase activation in axotomized retinal ganglion cells. Mol Cell Neurosci 25:383–393

    Article  PubMed  CAS  Google Scholar 

  • Dawson TM (2002) Preconditioning-mediated neuroprotection through erythropoietin? Lancet 359:96–97

    Article  PubMed  Google Scholar 

  • Diem R, Sattler MB, Merkler D, Demmer I, Maier K, Stadelmann C, Ehrenreich H, Bahr M (2005) Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 128:375–385

    Article  PubMed  Google Scholar 

  • Erbayraktar S et al (2003) Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci USA 100:6741–6746

    Article  PubMed  CAS  Google 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 99:9450–9455

    Article  PubMed  CAS  Google 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 4:310–318

    Article  PubMed  Google Scholar 

  • Grimm C, Wenzel A, Groszer M, Mayser H, Seeliger M, Samardzija M, Bauer C, Gassmann M, Reme CE (2002) HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 8:718–724

    Article  PubMed  CAS  Google Scholar 

  • Grimm C, Wenzel A, Stanescu D, Samardzija M, Hotop S, Groszer M, Naash M, Gassmann M, Reme C (2004) Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration. J Neurosci 24:5651–5658

    Article  PubMed  CAS  Google Scholar 

  • Jelkmann W, Metzen E (1996) Erythropoietin in the control of red cell production. Ann Anat 178:391–403

    PubMed  CAS  Google Scholar 

  • Ji JZ, Elyaman W, Yip HK, Lee VW, Yick LW, Hugon J, So KF (2004) CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway. Eur J Neurosci 19:265–272

    Article  PubMed  Google Scholar 

  • Junk AK, Mammis A, Savitz SI, Singh M, Roth S, Malhotra S, Rosenbaum PS, Cerami A, Brines M, Rosenbaum DM (2002) Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci USA 99:10659–10664

    Article  PubMed  CAS  Google Scholar 

  • Juul SE, Anderson DK, Li Y, Christensen RD (1998) Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr Res 43:40–49

    Article  PubMed  CAS  Google Scholar 

  • Kilic U, Kilic E, Soliz J, Bassetti CI, Gassmann M, Hermann DM (2005) Erythropoietin protects from axotomy-induced degeneration of retinal ganglion cells by activating ERK-1/-2. FASEB J 19:249–251

    PubMed  CAS  Google Scholar 

  • Kocsis I, Treszl A, Vasarhelyi B (2005) Role of erythropoietin in brain homeostasis, neurodevelopment and neuroprotection. Orv Hetil 146:2527–2532

    PubMed  Google Scholar 

  • Kretz A, Happold CJ, Marticke JK, Isenmann S (2005) Erythropoietin promotes regeneration of adult CNS neurons via Jak2/Stat3 and PI3K/AKT pathway activation. Mol Cell Neurosci 29:569–579

    Article  PubMed  CAS  Google Scholar 

  • Morrison JC, Johnson EC, Cepurna W, Jia L (2005) Understanding mechanisms of pressure-induced optic nerve damage. Prog Retin Eye Res 24:217–240

    Article  PubMed  Google Scholar 

  • Osborne NN, Ugarte M, Chao M, Chidlow G, Bae JH, Wood JP, Nash MS (1999) Neuroprotection in relation to retinal ischemia and relevance to glaucoma. Surv Ophthalmol 43(Suppl 1):S102–S128

    Article  PubMed  Google Scholar 

  • Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ (1995) Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 36:774–786

    PubMed  CAS  Google Scholar 

  • Rex TS, Allocca M, Domenici L, Surace EM, Maguire AM, Lyubarsky A, Cellerino A, Bennett J, Auricchio A (2004) Systemic but not intraocular Epo gene transfer protects the retina from light-and genetic-induced degeneration. Mol Ther 10:855–861

    Article  PubMed  CAS  Google Scholar 

  • Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, Sakaki S, Masuda S, Sasaki R (1998) Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun 253:26–32

    Article  PubMed  CAS  Google Scholar 

  • Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 95:4635–4640

    Article  PubMed  CAS  Google Scholar 

  • Sattler MB, Merkler D, Maier K, Stadelmann C, Ehrenreich H, Bahr M, Diem R (2004) Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis. Cell Death Differ 11(Suppl 2):S181–S192

    Article  PubMed  Google Scholar 

  • Schori H, Kipnis J, Yoles E, WoldeMussie E, Ruiz G, Wheeler LA, Schwartz M (2001) Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci USA 98:3398–3403

    Article  PubMed  CAS  Google Scholar 

  • Siren AL, Ehrenreich H (2001) Erythropoietin – a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci 251:179–184

    Article  PubMed  CAS  Google 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 98:4044–4049

    Article  PubMed  CAS  Google Scholar 

  • Sommer A (1989) Intraocular pressure and glaucoma. Am J Ophthalmol 107:186–188

    PubMed  CAS  Google Scholar 

  • Tsai JC, Wu L, Worgul B, Forbes M, Cao J (2005) Intravitreal administration of erythropoietin and preservation of retinal ganglion cells in an experimental rat model of glaucoma. Curr Eye Res 30:1025–1031

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Zhu C, Wang X, Gerwien JG, Schrattenholz A, Sandberg M, Leist M, Blomgren K (2004) The nonerythropoietic asialoerythropoietin protects against neonatal hypoxia-ischemia as potently as erythropoietin. J Neurochem 91:900–910

    Article  PubMed  CAS  Google Scholar 

  • Weishaupt JH, Rohde G, Polking E, Siren AL, Ehrenreich H, Bahr M (2004) Effect of erythropoietin axotomy-induced apoptosis in rat retinal ganglion cells. Invest Ophthalmol Vis Sci 45:1514–1522

    Article  PubMed  Google Scholar 

  • WoldeMussie E, Ruiz G, Wijono M, Wheeler LA (2001) Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Invest Ophthalmol Vis Sci 42:2849–2855

    PubMed  CAS  Google Scholar 

  • Yamasaki M, Mishima HK, Yamashita H, Kashiwagi K, Murata K, Minamoto A, Inaba T (2005) Neuroprotective effects of erythropoietin on glutamate and nitric oxide toxicity in primary cultured retinal ganglion cells. Brain Res 1050:15–26

    Article  PubMed  CAS  Google Scholar 

  • Zhong L, Bradley J, Schubert W, Ahmed E, Adamis AP, Shima DT, Robinson GS, Ng YS (2007) Erythropoietin promotes survival of retinal ganglion cells in DBA/2J glaucoma mice. Invest Ophthalmol Vis Sci 48:1212–1218

    Article  PubMed  Google Scholar 

Download references

Acknowledgement

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.

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Authors and Affiliations

  1. Department of Anatomy, The University of Hong Kong Li Ka Shing Faculty of Medicine, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China

    Qing-Ling Fu, Wutian Wu, Hua Wang, Xin Li & Kwok-Fai So

  2. The State Key Laboratory of Brain and Cognitive sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China

    Qing-Ling Fu, Wutian Wu, Hua Wang, Xin Li & Kwok-Fai So

  3. Eye Centre, Hong Kong Adventist Hospital, Hong Kong, Hong Kong SAR, China

    Vincent W. H. Lee

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  1. Qing-Ling Fu
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  2. Wutian Wu
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  3. Hua Wang
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  4. Xin Li
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  5. Vincent W. H. Lee
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Correspondence to Kwok-Fai So.

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Fu, QL., Wu, W., Wang, H. et al. Up-regulated Endogenous Erythropoietin/Erythropoietin Receptor System and Exogenous Erythropoietin Rescue Retinal Ganglion Cells after Chronic Ocular Hypertension. Cell Mol Neurobiol 28, 317–329 (2008). https://doi.org/10.1007/s10571-007-9155-z

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  • DOI: https://doi.org/10.1007/s10571-007-9155-z

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