Tissue Protective Activities of Erythropoietin

  • N. S. A. Patel
  • M. M. Yaqoob
  • C. Thiemermann
Conference paper


Erythropoietin (EPO) is a 165 amino acid glycoprotein hormone (30.4 kDa) member of the type 1 cytokine superfamily that is produced primarily by renal cortical and outer medullary type 1 fibroblasts [1] in response to tissue hypoxia under the control of the oxygen-sensitive transcription factor hypoxia-inducible factor-l (HIF-l). EPO binds to a preformed EPO receptor homodimer (EPOR)2 present on the cell membrane of erythrocyte progenitors. On activation of (EPOR)2 a molecular cascade begins with the phosphorylation of Janus tyrosine kinase 2, which ultimately results in inhibition of programmed cell death, principally involving Akt and the Bcl-2 gene family, resulting in the survival and maturation of erythroid progenitor cells to erythrocytes [2]. The overall effect is a compensatory adaptation to tissue hypoxia by enhancing the oxygen-carrying capacity of the blood [3], and thus may be therapeutically useful for the treatment of anemia associated with chronic kidney disease or chemotherapy [4, 5, 6].


Erythropoietin Receptor Erythroid Progenitor Cell Endothelial Progenitor Cell Mobilization Plasma Aspartate Aminotransferase Minute Ischemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Johnson DW, Forman C, Vesey DA (2006) Novel renoprotective actions of erythropoietin: New uses for an old hormone. Nephrology (Carlton) 11: 306–312CrossRefPubMedGoogle Scholar
  2. 2.
    Jelkmann W (1992) Erythropoietin: Structure, control of production, and function. Physiol Rev 72: 449–489Google Scholar
  3. 3.
    Fisher JW (2003) Erythropoietin: Physiology and pharmacology update. Exp Biol Med (Maywood) 228: 1–14Google Scholar
  4. 4.
    Adamson W, Egrie JC, Browne JK, Downing MR, Eschbach W (1988) The use of recombinant human erythropoietin (EPa) to correct the anemia of end-stage renal disease: A progress report. Behring Inst Mitt 188-192Google Scholar
  5. 5.
    Drueke TB, Locatelli F, Clyne N, et al (2006) Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355: 2071–2084CrossRefPubMedGoogle Scholar
  6. 6.
    Oster W, Herrmann F, Gamm H, et al (1990) Erythropoietin for the treatment of anemia of malignancy associated with neoplastic bone marrow infiltration. J Clin Oncol 8: 956–962Google Scholar
  7. 7.
    Abdelrahman M, Sharples EJ, McDonald MC, et al (2004) Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia. Shock 22: 63–69CrossRefPubMedGoogle Scholar
  8. 8.
    Calvillo L, Latini R, Kajstura J, et al (2003) Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Nat! Acad Sci USA 100: 4802–4806CrossRefPubMedGoogle Scholar
  9. 9.
    Heeschen C, Aicher A, Lehmann R, et al (2003) Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 102: 1340–1346CrossRefPubMedGoogle Scholar
  10. 10.
    Patel NS, Sharples EJ, Cuzzocrea S, et al (2004) Pretreatment with EPa reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo. Kidney Int 66: 983–989CrossRefPubMedGoogle Scholar
  11. 11.
    Sakanaka M, Wen TC, Matsuda S, et al (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Nat! Acad Sci USA 95: 4635–4640CrossRefPubMedGoogle Scholar
  12. 12.
    Sharples EJ, Patel N, Brown P, et al (2004) Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol 15: 2115–2124CrossRefPubMedGoogle Scholar
  13. 13.
    van Wijk SJ, Hageman GJ (2005) Poly(adp-ribose) polymerase-l mediated caspase-indepen dent cell death after ischemia/reperfusion. Free Radic Biol Med 39: 81–90PubMedGoogle Scholar
  14. 14.
    Gourdin MJ, Bree B) De Kock M (2009) The impact of ischaemia-reperfusion on the blood vessel. Eur J Anaesthesiol 26: 537–547CrossRefPubMedGoogle Scholar
  15. 15.
    Lenz A, Franklin GA, Cheadle WG (2007) Systemic inflammation after trauma. Injury 38: 1336–1345CrossRefPubMedGoogle Scholar
  16. 16.
    van Griensven M, Stalp M, Seekamp A (1999) Ischemia-reperfusion directly increases pulmonary endothelial permeability in vitro. Shock 11: 259–263CrossRefPubMedGoogle Scholar
  17. 17.
    Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R (1997) Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76: 105–116CrossRefPubMedGoogle Scholar
  18. 18.
    Wright GL, Hanlon P, Amin K, Steenbergen C, Murphy E, Arcasoy MO (2004) Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB J 18: 1031–1033PubMedGoogle Scholar
  19. 19.
    Depping R, Kawakami K, Ocker H, et al (2005) Expression of the erythropoietin receptor in human heart. J Thorac Cardiovasc Surg 130: 877–878CrossRefPubMedGoogle Scholar
  20. 20.
    Pars a CJ, Matsumoto A, Kim J, et al (2003) A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112: 999–1007PubMedGoogle Scholar
  21. 21.
    Westenfelder C, Biddle DL, Baranowski RL (1999) Human, rat, and mouse kidney cells express functional erythropoietin receptors. Kidney Int 55: 808–820CrossRefPubMedGoogle Scholar
  22. 22.
    Yang CW, Li C, Jung JY, et al (2003) Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney. FASEB J 17: 1754–1755CrossRefPubMedGoogle Scholar
  23. 23.
    Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M (1990) Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci USA 87: 5978–5982CrossRefPubMedGoogle Scholar
  24. 24.
    Bahlmann FH, DeGroot K, Duckert T, et al (2003) Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int 64: 1648–1652CrossRefPubMedGoogle Scholar
  25. 25.
    Aoshiba K, Onizawa S, Tsuji T, Nagai A (2009) Therapeutic effects of erythropoietin in murine models of endotoxin shock. Crit Care Med 37: 889–898CrossRefGoogle Scholar
  26. 26.
    Genc K, Genc S, Baskin H, Semin I (2006) Erythropoietin decreases cytotoxicity and nitric oxide formation induced by inflammatory stimuli in rat oligodendrocytes. Physiol Res 55: 33–38Google Scholar
  27. 27.
    Cuzzocrea S, Di Paola R, Mazzon E, et al (2006) Erythropoietin reduces the development of nonseptic shock induced by zymosan in mice. Crit Care Med 34: 1168–1177CrossRefGoogle Scholar
  28. 28.
    Cuzzocrea S, Mazzon E, di Paola R, et al (2005) Erythropoietin reduces the degree of arthritis caused by type ii collagen in the mouse. Arthritis Rheum 52: 940–950CrossRefGoogle Scholar
  29. 29.
    Nagai A, Nakagawa E, Choi HB, Hatori K, Kobayashi S, Kim SU (2001) Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. J Neuropathol Exp Neurol 60: 386–392PubMedGoogle Scholar
  30. 30.
    Sela S, Shurtz-Swirski R, Sharon R, et al (2001) The polymorphonuclear leukocyte—a new target for erythropoietin. Nephron 88: 205–210CrossRefPubMedGoogle Scholar
  31. 31.
    Digicaylioglu M, Bichet S, Marti HH, et al (1995) Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci USA 92: 3717–3720CrossRefPubMedGoogle Scholar
  32. 32.
    Villa P, Bigini P, Mennini T, et al (2003) Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med 198: 971–975CrossRefPubMedGoogle Scholar
  33. 33.
    Ehrenreich H, Hasselblatt M, Dembowski C, et al (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8: 495–505PubMedGoogle Scholar
  34. 34.
    Minino AM, Anderson RN, Fingerhut LA, Boudreault MA, Warner M (2006) Deaths: Injuries, 2002. Natl Vital Stat Rep 54: 1–124Google Scholar
  35. 35.
    Shapiro MJ, Gettinger A, Corwin HL, et al (2003) Anemia and blood transfusion in trauma patients admitted to the intensive care unit. J Trauma 55: 269–273CrossRefPubMedGoogle Scholar
  36. 36.
    Corwin HL, Gettinger A, Rodriguez RM, et al (1999) Efficacy of recombinant human erythropoietin in the critically ill patient: A randomized, double-blind, placebo-controlled trial. Crit Care Med 27: 2346–2350CrossRefPubMedGoogle Scholar
  37. 37.
    Corwin HL, Gettinger A, Pearl RG, et al (2002) Efficacy of recombinant human erythropoietin in critically ill patients: A randomized controlled trial. JAMA 288: 2827–2835CrossRefPubMedGoogle Scholar
  38. 38.
    Corwin HL, Gettinger A, Fabian TC, et al (2007) Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 357: 965–976CrossRefPubMedGoogle Scholar
  39. 39.
    Napolitano LM, Fabian TC, Kelly KM, et al (2008) Improved survival of critically ill trauma patients treated with recombinant human erythropoietin. J Trauma 65: 285–297CrossRefPubMedGoogle Scholar
  40. 40.
    McCaffery PJ, Fraser JK, Lin FK, Berridge MV (1989) Subunit structure of the erythropoietin receptor. J BioI Chern 264: 10507–10512Google Scholar
  41. 41.
    Goodman JW, Hall EA, Miller KL, Shinpock SG (1985) Interleukin 3 promotes erythroid burst formation in “serum-free” cultures without detectable erythropoietin. Proc Nat! Acad Sci USA 82: 3291–3295CrossRefPubMedGoogle Scholar
  42. 42.
    Monette FC, Sigounas G (1988) Growth of murine multipotent stem cells in a simple “serumfree” culture system: Role of interleukin-3, erythropoietin, and hemin. Exp Hematol 16: 250–255PubMedGoogle Scholar
  43. 43.
    Sieff CA, Ekern SC, Nathan DG, Anderson JW (1989) Combinations of recombinant colonystimulating factors are required for optimal hematopoietic differentiation in serum-deprived culture. Blood 73: 688–693PubMedGoogle Scholar
  44. 44.
    Brines M, Grasso G, Fiordaliso F, et al (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Nat! Acad Sci USA 101: 14907–14912CrossRefPubMedGoogle Scholar
  45. 45.
    Jubinsky PT, Krijanovski 01, Nathan DG, Tavernier J, Sieff CA (1997) The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor. Blood 90: 1867–1873PubMedGoogle Scholar
  46. 46.
    Leist M, Ghezzi P, Grasso G, et al (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305: 239–242CrossRefPubMedGoogle Scholar
  47. 47.
    Brines M, Patel NS, Villa P, et al (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Nat! Acad Sci USA 105: 10925–10930CrossRefPubMedGoogle Scholar
  48. 48.
    Lai SY, Childs EE, Xi S, et al (2005) Erythropoietin-mediated activation of jak-stat signaling contributes to cellular invasion in head and neck squamous cell carcinoma. Oncogene 24: 4442–4449CrossRefPubMedGoogle Scholar
  49. 49.
    Machtay M, Pajak TF, Suntharalingam M, et al (2007) Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: A randomized trial of the radiation therapy oncology group (rtog 99–03). Int J Radiat Oncol Biol Phys 69: 1008–1017CrossRefPubMedGoogle Scholar
  50. 50.
    Lambin P, Ramaekers BL, van Mastrigt GA, et al (2009) Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer. Cochrane Database Syst Rev CD006158Google Scholar

Copyright information

© Springer Science + Business Media Inc. 2010

Authors and Affiliations

  • N. S. A. Patel
    • 1
  • M. M. Yaqoob
    • 1
  • C. Thiemermann
  1. 1.The William Harvey Research InstituteQueen Mary University of London Centre for Translational Medicine and TherapeuticsLondonUK

Personalised recommendations