Abstract
The oxygen-dependent, renal cytokine eythropoietin (Epo) is well known to increase red cell production. Binding of Epo to the Epo receptor (EpoR) represses apoptosis of erythroid progenitor cells, thereby allowing their final maturation. We and others showed that Epo and its receptor are expressed in many other tissues, including brain, spinal cord, retina and testis. The presence of a blood barrier suggests that Epo plays a local role in these organs. Indeed, therapeutically applied or hypoxically induced Epo has been shown to reduce the infarct volume in various stroke animal models, to prevent retinal degeneration, and to ameliorate spinal cord injury. In a study conducted by Ehrenreich and colleagues, stroke patients treated with Epo showed reduced infarct volume, fast neurological recovery and improved clinical outcome. In analogy to its function on erythroid progenitor cells, this neuroprotective effect of Epo might be explained by repression of programmed cell death. Apart from neuroprotection, there is an assumption that Epo present in breast milk has the potential to protect against mother-to-infant transmission of HIV. When using Epo at high doses for longer time periods; however, care has to be taken to control the resulting chronic polycythemia that most probably caused enlarged cerebral infarct volumes in a transgenic mouse model that due to Epo-overexpression reached hematocrit levels of about 0.8. Overall, these data strongly support the notion that Epo will soon find new applications in the clinic.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bernaudin M, Bellail A, Marti HH, Yvon A, Vivien D, Duchatelle I, MacKenzie ET, and Petit E. Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia 30: 271–278, 2000.
Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, and Petit E. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19: 643–651, 1999.
Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, and Cerami A. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 97: 10526–10531, 2000.
Buemi M, Allegra A, Corica F, Floccari F, D’Avella D, Aloisi C, Calapai G, Iacopino G, and Frisina N. Intravenous recombinant erythropoietin does not lead to an increase in cerebrospinal fluid erythropoietin concentration. Nephrol Dial Transplant 15: 422–423, 2000.
Calapai G, Marciano MC, Corica F, Allegra A, Parisi A, Frisina N, Caputi AP, and Buemi M. Erythropoietin protects against brain ischemic injury by inhibition of nitric oxide formation. Eur J Pharmacol 401: 349–356, 2000.
Cehk M, Gökmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C, Gene S, Gene K, Sagiroglu E, Cerami A, and Brines M. Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA 99: 2258–2263, 2002.
Cerami A, Brines M, Ghezzi P, Cerami C, and Itri LM. Neuroprotective properties of epoetin alfa. Nephrol Dial Transplant 17 Suppl 1: 8–12, 2002.
Chikuma M, Masuda S, Kobayashi T, Nagao M, and Sasaki R. Tissue-specific regulation of erythropoietin production in the murine kidney, brain, and uterus. Am J Physiol 279: E1242– E1248, 2000.
Chin K, Yu X, Beleslin-Cokic B, Liu C, Shen K, Mohrenweiser HW, and Noguchi CT. Production and processing of erythropoietin receptor transcripts in brain. Brain Res Mol Brain Res 81: 29–42, 2000.
Dame C, Juul SE, and Christensen RD. The biology of erythropoietin in the central nervous system and its neurotrophic and neuroprotective potential. Biol Neonate 79: 228–235, 2001.
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.
Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bonn 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.
Goldman SA and Nedergaard M. Erythropoietin strikes a new cord. Nat Med 8: 785–787, 2002.
Gorio A, Gkmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Vardar E, Cerami A, and Brines M. Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci USA 99: 9450–9455, 2002.
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.
Harrison MJ, Pollock S, Kendall BE, and Marshall J. Effect of haematocrit on carotid stenosis and cerebral infarction. Lancet 2: 114–115, 1981.
Hofer T, Wenger RH, and Gassmann M. Oxygen sensing, HIF-1α stabilization and potential therapeutic strategies. Pflugers Archiv - Eur J Physiol 443: 503–507, 2002.
Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev 72: 449–489, 1992.
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.
Juul SE, Joyce AE, Zhao Y, and Ledbetter DJ. Why is erythropoietin present in human milk? Studies of erythropoietin receptors on enterocytes of human and rat neonates. Pediatr Res 46: 263–268, 1999.
Juul SE, Zhao Y, Dame JB, Du Y, Hutson AD, and Christensen RD. Origin and fate of erythropoietin in human milk. Pediatr Res 48: 660–667, 2000.
Kawakami M, Sekiguchi M, Sato K, Kozaki S, and Takahashi M. Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia. J Biol Chem 276: 39469–39475, 2001.
Kling PJ, Sullivan TM, Roberts RA, Philipps AF, and Koldovsky O. Human milk as a potential enteral source of erythropoietin. Pediatr Res 43: 216–221, 1998.
Koury MJ and Bondurant MC. Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science 248: 378–381, 1990.
Magnanti M, Gandini O, Giuliani L, Gazzaniga P, Marti HH, Gradilone A, Frati L, Agliano AM, and Gassmann M. Erythropoietin expression in primary rat Sertoli and peritubular myoid cells. Blood 98: 2872–2874, 2001.
Marti HH and Bernaudin M. Function of erythropoietin in the brain. In: Erythropoietin: Molecular biology and clinical use. FP Graham Publishing Co (Johnson city): 195–215, 2003.
Marti HH, Bernaudin M, Petit E, and Bauer C. Neuroprotection and angiogenesis: A dual role of erythropoietin in brain ischemia. News Physiol Sci 15: 225–229, 2000.
Marti HH, Gassmann M, Wenger RH, Kvietikova I, Morganti-Kossmann MC, Kossmann T, Trentz O, and Bauer C. Detection of erythropoietin in human liquor: Intrinsic erythropoietin production in the brain. Kidney Int 51: 416–418, 1997.
Marti HH, Wenger RH, Rivas LA, Straumann U, Digicaylioglu M, Henn V, Yonekawa Y, Bauer C, and Gassmann M. Erythropoietin gene expression in human, monkey and murine brain. Eur JNeurosci 8: 666–676, 1996.
Masuda S, Chikuma M, and Sasaki R. Insulin-like growth factors and insulin stimulate erythropoietin production in primary cultured astrocytes. Brain Res 746: 63–70, 1997.
Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, and Sasaki R. A novel site of erythropoietin production: oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269: 19488–19493, 1994.
Miller M, Iliff P, Stoltzfus RJ, and Humphrey J. Breastmilk erythropoietin and mother-to-child HIV transmission through breastmilk. Lancet 360: 1246–1248, 2002.
Morishita E, Masuda S, Nagao M, Yasuda Y, and Sasaki R. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76: 105–116, 1997.
Nagai A, Nakagawa E, Choi HB, Hatori K, Kobayashi S, and Kim SU. Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. J Neuropathol Exp Neurol 60: 386–392, 2001.
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.
Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, Sakaki S, Masuda S, and Sasaki R. 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, 1998.
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 Sei USA 95: 4635–4640, 1998.
Sasaki R, Masuda S, and Nagao M. Pleiotropic functions and tissue-specific expression of erythropoietin. News Physiol Sci 16: 110–113, 2001.
Silva M, Grillot D, Benito A, Richard C, Nunez G, and Fernandez-Luna JL. Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through bcl-xL and bcl-2. Blood 88: 1576–1582, 1996.
Siren AL, Knerlich F, Poser W, Gleiter CH, Brück W, and Ehrenreich H. Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol 101: 271–276, 2001.
Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, 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.
Tan CC, Eckardt K-U, 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– F481, 1992.
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.
Wiessner C, Allegrini PR, Ekatodramis D, Jewell UR, Stallmach T, and Gassmann M. Increased cerebral infarct volumes in polyglobulic mice overexpressing erythropoietin. J Cereb Blood Flow Metab 21: 857–864, 2001.
Wrighton NC, Farrell FX, Chang R, Kashyap AK, Barbone FP, Mulcahy LS, Johnson DL, Barrett RW, Jolliffe LK, and Dower WJ. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273: 458–463, 1996.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer Science+Business Media New York
About this paper
Cite this paper
Gassmann, M., Heinicke, K., Soliz, J., Ogunshola, O.O. (2003). Non-Erythroid Functions of Erythropoietin. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (eds) Hypoxia. Advances in Experimental Medicine and Biology, vol 543. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8997-0_22
Download citation
DOI: https://doi.org/10.1007/978-1-4419-8997-0_22
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-4753-8
Online ISBN: 978-1-4419-8997-0
eBook Packages: Springer Book Archive