Hypoxic Preconditioning and Erythropoietin Protect Retinal Neurons from Degeneration

  • Christian Grimm
  • A. Wenzel
  • N. Acar
  • S. Keller
  • M. Seeliger
  • Max Gassmann
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 588)


Reduced tissue oxygenation stabilizes the alpha-subunit of the transcription factor hypoxia-inducible factor-1 (HIF-1). This leads to the induction of a number of hypoxia responsive genes. One of the best known HIF-1 targets is erythropoietin that exerts neuroprotective effects on ischemia-related injury in the brain. Thus, pre-exposure to low environmental oxygen concentrations might be exploited as a preconditioning procedure to protect tissues against a variety of harmful conditions. We present recent work on neuroprotection of retinal photoreceptors induced by hypoxic preconditioning or by systemically elevated levels of Epo in mouse plasma.

Key Words

hypoxia-inducible factor-1 apoptosis photoreceptor blinding disease overexpression of EPO 


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  1. 1.
    Barbe MF, Tytell M, Gower DJ, and Welch WJ. Hyperthermia protects against light damage in the rat retina. Science 241: 1817–1820, 1988.PubMedCrossRefGoogle Scholar
  2. 2.
    Brinchmann-Hansen O and Myhre K. The effect of hypoxia upon macular recovery time in normal humans. Aviat Space Environ Med 60: 1183–1186, 1989.PubMedGoogle Scholar
  3. 3.
    Camenisch G, Stroka DM, Gassmann M, and Wenger RH. Attenuation of HIF-1 DNA-binding activity limits hypoxia-inducible endothelin-1 expression. Pflugers Arch 443: 240–249, 2001.PubMedCrossRefGoogle Scholar
  4. 4.
    Camenisch G, Tini M, Chilov D, Kvietikova I, Srinivas V, Caro J, Spielmann P, Wenger RH, and Gassmann M. General applicability of chicken egg yolk antibodies: the performance of IgY immunoglobulins raised against the hypoxia-inducible factor 1alpha. FasebJ 13: 81–88, 1999.Google Scholar
  5. 5.
    Casson RJ, Chidlow G, Wood JP, Vidal-Sanz M, and Osborne NN. The effect of retinal ganglion cell injury on light-induced photoreceptor degeneration. Invest Ophthalmol Vis Sci 45: 685–693, 2004.PubMedCrossRefGoogle Scholar
  6. 6.
    Casson RJ, Wood JP, Melena J, Chidlow G, and Osborne NN. The effect of ischemic preconditioning on light-induced photoreceptor injury. Invest Ophthalmol Vis Sci 44: 1348–1354, 2003.PubMedCrossRefGoogle Scholar
  7. 7.
    Chang B, Hawes NL, Hurd RE, Davisson MT, Nusinowitz S, and Heckenlively JR. Retinal degeneration mutants in the mouse. Vision Res 42: 517–525, 2002.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen CK, Burns ME, Spencer M, Niemi GA, Chen J, Hurley JB, Baylor DA, and Simon MI. Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase. Proc Natl Acad Sci USA 96: 3718–3722, 1999.PubMedCrossRefGoogle Scholar
  9. 9.
    Chen J, Simon MI, Matthes MT, Yasumura D, and LaVail MM. Increased susceptibility to light damage in an arrestin knockout mouse model of Oguchi disease (stationary night blindness). Invest Ophthalmol Vis Sci 40: 2978–2982, 1999.PubMedGoogle Scholar
  10. 10.
    Cideciyan AV, Hood DC, Huang Y, Banin E, Li ZY, Stone EM, Milam AH, and Jacobson SG. Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man. Proc Natl Acad Sci USA 95: 7103–7108, 1998.PubMedCrossRefGoogle Scholar
  11. 11.
    Cruickshanks KJ, Klein R, and Klein BE. Sunlight and age-related macular degeneration. The Beaver Dam Eye Study. Arch Ophthalmol 111: 514–518, 1993.Google Scholar
  12. 12.
    Cruickshanks KJ, Klein R, Klein BE, and Nondahl DM. Sunlight and the 5-year incidence of early age-related maculopathy: the beaver dam eye study. Arch Ophthalmol 119: 246–250, 2001.PubMedGoogle Scholar
  13. 13.
    Digicaylioglu M, Bichet S, Marti HH, Wenger RH, Rivas LA, Bauer C, and Gassmann M. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci USA 92: 3717–3720., 1995.PubMedCrossRefGoogle Scholar
  14. 14.
    Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, and Siren AL. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8: 495–505, 2002.PubMedGoogle Scholar
  15. 15.
    Eid T and Brines M. Recombinant human erythropoietin for neuroprotection: what is the evidence? Clin Breast Cancer 3Suppl 3: S109–115, 2002.PubMedGoogle Scholar
  16. 16.
    Eisen A, Fisman EZ, Rubenfire M, Freimark D, McKechnie R, Tenenbaum A, Motro M, and Adler Y Ischemic preconditioning: nearly two decades of research. A comprehensive review. Atherosclerosis 172: 201–210, 2004.PubMedCrossRefGoogle Scholar
  17. 17.
    Gassmann M, Heinicke K, Soliz J, and Ogunshola OO. Non-erythroid functions of erythropoietin. Adv Exp Med Biol 543: 323–330, 2003.PubMedGoogle Scholar
  18. 18.
    Ghezzi P and Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ 11Suppl 1: S37–44, 2004.PubMedCrossRefGoogle Scholar
  19. 19.
    Goto Y, Peachey NS, Ziroli NE, Seiple WH, Gryczan C, Pepperberg DR, and Naash MI. Rod phototransduction in transgenic mice expressing a mutant opsin gene. J Opt Soc Am A 13: 577–585., 1996.Google Scholar
  20. 20.
    Grimm C, Wenzel A, Groszer M, Mayser H, Seeliger M, Samardzija M, Bauer C, Gassmann M, and Reme CE. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 8: 718–724, 2002.PubMedCrossRefGoogle Scholar
  21. 21.
    Grimm C, Wenzel A, Stanescu D, Samardzija M, Hotop S, Groszer M, Naash M, Gassmann M, and Reme C. Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration. J Neurosci 24: 5651–5658, 2004.PubMedCrossRefGoogle Scholar
  22. 22.
    Hafezi F, Grimm C, Simmen BC, Wenzel A, and Reme CE. Molecular ophthalmology: an update on animal models for retinal degenerations and dystrophies. Br J Ophthalmol 84: 922–927, 2000.PubMedCrossRefGoogle Scholar
  23. 23.
    Hafezi F, Steinbach JP, Marti A, Munz K, Wang ZQ, Wagner EF, Aguzzi A, and Reme CE. The absence of c-fos prevents light-induced apoptotic cell death of photoreceptors in retinal degeneration in vivo. Nat Med 3: 346–349, 1997.PubMedCrossRefGoogle Scholar
  24. 24.
    Hopfl G, Ogunshola O, and Gassmann M. HIFs and tumors-causes and consequences. Am J Physiol Regul Integr Comp Physiol 286: R608–623, 2004.PubMedGoogle Scholar
  25. 25.
    Hopfl G, Ogunshola O, and Gassmann M. Hypoxia and high altitude. The molecular response. Adv Exp Med Biol 543: 89–115, 2003.PubMedGoogle Scholar
  26. 26.
    Huttl S, Michalakis S, Seeliger M, Luo DG, Acar N, Geiger H, Hudl K, Mader R, Haverkamp S, Moser M, Pfeifer A, Gerstner A, Yau KW, and Biel M. Impaired channel targeting and retinal degeneration in mice lacking the cyclic nucleotide-gated channel subunit CNGB1. J Neurosci 25: 130–138, 2005.PubMedCrossRefGoogle Scholar
  27. 27.
    Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev 72:449–489., 1992.PubMedGoogle Scholar
  28. 28.
    Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, and Gassmann M. Induction of HIF-1 alpha in response to hypoxia is instantaneous. Faseb J 15: 1312–1314., 2001.PubMedGoogle Scholar
  29. 29.
    Junk AK, Mammis A, Savitz SI, Singh M, Roth S, Malhotra S, Rosenbaum PS, Cerami A, Brines M, and Rosenbaum DM. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci U S A 99: 10659–10664, 2002.PubMedCrossRefGoogle Scholar
  30. 30.
    Kaldi I, Martin RE, Huang H, Brush RS, Morrison KA, and Anderson RE. Bright cyclic rearing protects albino mouse retina against acute light-induced apoptosis. Mol Vis 9: 337–344, 2003.PubMedGoogle Scholar
  31. 31.
    Keller C, Grimm C, Wenzel A, Hafezi F, and Reme C. Protective effect of halothane anesthesia on retinal light damage: inhibition of metabolic rhodopsin regeneration. Invest Ophthalmol Vis Sci 42: 476–480, 2001.PubMedGoogle Scholar
  32. 32.
    Kobrick JL, Zwick H, Witt CE, and Devine JA. Effects of extended hypoxia on night vision. Aviat Space Environ Med 55: 191–195, 1984.PubMedGoogle Scholar
  33. 33.
    LaVail MM, Gorrin GM, Yasumura D, and Matthes MT. Increased susceptibility to constant light in nr and pcd mice with inherited retinal degeneration. Invest Ophthalmol Vis Sci 40: 1020–1024, 1999.PubMedGoogle Scholar
  34. 34.
    Leber LL, Roscoe SN, and Southward GM. Mild hypoxia and visual performance with night vision goggles. Aviat Space Environ Med 57:318–324, 1986.PubMedGoogle Scholar
  35. 35.
    Li F, Cao W, and Anderson RE. Protection of photoreceptor cells in adult rats from light-induced degeneration by adaptation to bright cyclic light. Exp Eye Res 73: 569–577, 2001.PubMedCrossRefGoogle Scholar
  36. 36.
    Li Y, Roth S, Laser M, Ma JX, and Crosson CE. Retinal preconditioning and the induction of heat-shock protein 27. Invest Ophthalmol Vis Sci 44: 1299–1304, 2003.PubMedCrossRefGoogle Scholar
  37. 37.
    Liu C, Peng M, Laties AM, and Wen R. Preconditioning with bright light evokes a protective response against light damage in the rat retina. J Neurosci 18: 1337–1344, 1998.PubMedGoogle Scholar
  38. 38.
    Marti HH. Erythropoietin and the hypoxic brain. J Exp Biol 207: 3233–3242, 2004.PubMedCrossRefGoogle Scholar
  39. 39.
    Marti HH, Wenger RH, Rivas LA, Straumann U, Digicaylioglu M, Herrn V, Yonekawa Y, Bauer C, and Gassmann M. Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 8: 666–676., 1996.PubMedCrossRefGoogle Scholar
  40. 40.
    Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, and Risau W. Hypoxiainduced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156: 965–976., 2000.PubMedGoogle Scholar
  41. 41.
    Nir I, Harrison JM, Liu C, and Wen R. Extended photoreceptor viability by light stress in the RCS rats but not in the opsin P23H mutant rats. Invest Ophthalmol Vis Sci 42: 842–849, 2001.PubMedGoogle Scholar
  42. 42.
    Nir I, Liu C, and Wen R. Light treatment enhances photoreceptor survival in dystrophic retinas of Royal College of Surgeons rats. Invest Ophthalmol Vis Sci 40: 2383–2390, 1999.PubMedGoogle Scholar
  43. 43.
    O’Steen WK, Bare DJ, Tytell M, Morris M, and Gower DJ. Water deprivation protects photoreceptors against light damage. Brain Res 534: 99–105, 1990.PubMedCrossRefGoogle Scholar
  44. 44.
    Organisciak DT, Li M, Darrow RM, and Farber DB. Photoreceptor cell damage by light in young Royal College of Surgeons rats. Curr Eye Res 19: 188–196, 1999.PubMedCrossRefGoogle Scholar
  45. 45.
    Ostroy SE, Gaitatzes CG, and Friedmann AL. Hypoxia inhibits rhodopsin regeneration in the excised mouse eye. Invest Ophthalmol Vis Sci 34: 447–452, 1993.PubMedGoogle Scholar
  46. 46.
    Quaschning T, Ruschitzka F, Stallmach T, Shaw S, Morawietz H, Goettsch W, Hermann M, Slowinski T, Theuring F, Hocher B, Luscher TF, and Gassmann M. Erythropoietin-induced excessive erythrocytosis activates the tissue endothelin system in mice. Faseb J 17: 259–261, 2003.PubMedGoogle Scholar
  47. 47.
    Reme CE, Grimm C, Hafezi F, Iseli HP, and Wenzel A. Why study rod cell death in retinal degenerations and how? Doc Ophthalmol 106: 25–29, 2003.PubMedCrossRefGoogle Scholar
  48. 48.
    Reme CE, Grimm C, Hafezi F, Marti A, and Wenzel A. Apoptotic cell death in retinal degenerations. Prog Retin Eye Res 17: 443–464, 1998.PubMedCrossRefGoogle Scholar
  49. 49.
    Rex TS, Allocca M, Domenici L, Surace EM, Maguire AM, Lyubarsky A, Cellerino A, Bennett J, and Auricchio A. Systemic but not intraocular Epo gene transfer protects the retina from light-and genetic-induced degeneration. Mol Ther 10: 855–861, 2004.PubMedCrossRefGoogle Scholar
  50. 50.
    Ruschitzka FT, Wenger RH, Stallmach T, Quaschning T, de Wit C, Wagner K, Labugger R, Kelm M, Noll G, Rulicke T, Shaw S, Lindberg RL, Rodenwaldt B, Lutz H, Bauer C, Luscher TF, and Gassmann M. Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proc Natl Acad Sci USA 97: 11609–11613, 2000.PubMedCrossRefGoogle Scholar
  51. 51.
    Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, and Sasaki R. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 95: 4635–4640., 1998.PubMedCrossRefGoogle Scholar
  52. 52.
    Sanyal S and Hawkins RK. Development and degeneration of retina in rds mutant mice: effects of light on the rate of degeneration in albino and pigmented homozygous and heterozygous mutant and normal mice. Vision Res 26: 1177–1185, 1986.PubMedCrossRefGoogle Scholar
  53. 53.
    Schofield CJ and Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5:343–354, 2004.PubMedCrossRefGoogle Scholar
  54. 54.
    Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology 19: 176–182, 2004.PubMedCrossRefGoogle Scholar
  55. 55.
    Shibata J, Hasegawa J, Siemens HJ, Wolber E, Dibbelt L, Li D, Katschinski DM, Fandrey J, Jelkmann W, Gassmann M, Wenger RH, and Wagner KF. Hemostasis and coagulation at a hematocrit level of 0.85: functional consequences of erythrocytosis. Blood 101: 4416–4422, 2003.PubMedCrossRefGoogle Scholar
  56. 56.
    Sieving PA, Chaudhry P, Kondo M, Provenzano M, Wu D, Carlson TJ, Bush RA, and Thompson DA. Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc Natl Acad Sci U S A 98: 1835–1840, 2001.PubMedCrossRefGoogle Scholar
  57. 57.
    Simons K. Artificial light and early-life exposure in age-related macular degeneration and in cataractogenic phototoxicity. Arch Ophthalmol 111: 297–298, 1993.PubMedGoogle Scholar
  58. 58.
    Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DA, Bauer C, Gassmann M, and Candinas D. HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. Faseb J 15: 2445–2453., 2001.PubMedGoogle Scholar
  59. 59.
    Tan CC, Eckardt KU, Firth JD, and Ratcliffe PJ. Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am J Physiol 263: F474–481, 1992.PubMedGoogle Scholar
  60. 60.
    Taylor HR, Munoz B, West S, Bressler NM, Bressler SB, and Rosenthal FS. Visible light and risk of age-related macular degeneration. Trans Am Ophthalmol Soc 88: 163–173, 1990.PubMedGoogle Scholar
  61. 61.
    Vogel J, Kiessling I, Heinicke K, Stallmach T, Ossent P, Vogel O, Aulmann M, Frietsch T, Schmid-Schonbein H, Kuschinsky W, and Gassmann M. Transgenic mice overexpressing erythropoietin adapt to excessive erythrocytosis by regulating blood viscosity. Blood 102: 2278–2284, 2003.PubMedCrossRefGoogle Scholar
  62. 62.
    Wagner KF, Katschinski DM, Hasegawa J, Schumacher D, Meller B, Gembruch U, Schramm U, Jelkmann W, Gassmann M, and Fandrey J. Chronic inborn erythrocytosis leads to cardiac dysfunction and premature death in mice overexpressing erythropoietin. Blood 97:536–542, 2001.PubMedCrossRefGoogle Scholar
  63. 63.
    Wang M, Lam TT, Tso MO, and Naash MI. Expression of a mutant opsin gene increases the susceptibility of the retina to light damage. Vis Neurosci 14: 55–62, 1997.PubMedCrossRefGoogle Scholar
  64. 64.
    Wenzel A, Grimm C, Marti A, Kueng-Hitz N, Hafezi F, Niemeyer G, and Reme CE. c-fos controls the “private pathway” of light-induced apoptosis of retinal photoreceptors. J Neurosci 20: 81–88, 2000.PubMedGoogle Scholar
  65. 65.
    Wenzel A, Grimm C, Samardzija M, and Reme CE. The genetic modifier Rpe65Leu(450): effect on light damage susceptibility in c-Fos-deficient mice. Invest Ophthalmol Vis Sci 44: 2798–2802, 2003.PubMedCrossRefGoogle Scholar
  66. 66.
    Wenzel A, Grimm C, Samardzija M, and Reme CE. Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration. Prog Retin Eye Res 24: 275–306, 2005.PubMedCrossRefGoogle Scholar
  67. 67.
    Wenzel A, Grimm C, Seeliger MW, Jaissle G, Hafezi F, Kretschmer R, Zrenner E, and Reme CE. Prevention of photoreceptor apoptosis by activation of the glucocorticoid receptor. Invest Ophthalmol Vis Sci 42: 1653–1659, 2001.PubMedGoogle Scholar
  68. 68.
    Wenzel A, Reme CE, Williams TP, Hafezi F, and Grimm C. The Rpe65 Leu450Met variation increases retinal resistance against light-induced degeneration by slowing rhodopsin regeneration. J Neurosci 21: 53–58, 2001.PubMedGoogle Scholar
  69. 69.
    Zhang C, Rosenbaum DM, Shaikh AR, Li Q, Rosenbaum PS, Pelham DJ, and Roth S. Ischemic preconditioning attenuates apoptotic cell death in the rat retina. Invest Ophthalmol Vis Sci 43: 3059–3066, 2002.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Christian Grimm
    • 1
    • 4
  • A. Wenzel
    • 1
    • 4
  • N. Acar
    • 2
    • 4
  • S. Keller
    • 3
    • 4
  • M. Seeliger
    • 2
    • 4
  • Max Gassmann
    • 3
    • 4
  1. 1.Laboratory of Retinal Cell BiologyEye Hospital Zurich and Center for Integrative Human PhysiologyZurichSwitzerland
  2. 2.Retinal Electrodiagnostics Research GroupUniversitäts-Augenklinik TübingenTübingenGermany
  3. 3.Institute of Veterinary Physiology, Vetsuisse Faculty and Center for Integrative Human PhysiologyUniversity of ZurichZurichSwitzerland
  4. 4.OphthalmologyUniversity Eye Hospital ZurichZurichSwitzerland

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