Pediatric Nephrology

, Volume 21, Issue 12, pp 1785–1789 | Cite as

EPO: renoprotection beyond anemia correction

  • Danilo Fliser
  • Ferdinand H. Bahlmann
  • Hermann Haller
Editorial Commentary

Abstract

Until recently the major physiological function of erythropoietin (EPO) was thought to be the induction of erythropoiesis. However, a growing body of evidence indicates that EPO has tissue-protective properties and prevents ischemia induced tissue damage in several organs including the kidney. A pivotal intracellular pathway mediating the beneficial effects of EPO is the activation of Akt, i.e. serine/threonine protein kinase B. As a result, Akt phosphorylates the proapoptotic factor Bad, which in turn causes inhibition of programmed cell death (apoptosis). In the present article we review data on the non-hematological effects of recombinant human EPO (rHuEPO) in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogues substances that are not related to anemia correction.

Keywords

Akt activation Apoptosis Erythropoietin (EPO) Renoprotection 

Notes

Acknowledgement

The study was supported by grants from Amgen and Roche AG.

References

  1. 1.
    Bogoyevitch MA (2004) An update on the cardiac effects of erythropoietin cardioprotection by erythropoietin and the lessons learnt from studies in neuroprotection. Cardiovasc Res 63:208–216PubMedCrossRefGoogle Scholar
  2. 2.
    Bahlmann FH, De Groot K, Haller H, Fliser D (2004) Erythropoetin - is it more than correcting anemia? Nephrol Dial Transplant 19:20–22PubMedCrossRefGoogle Scholar
  3. 3.
    Brines M, Cerami A (2005) Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 6:484–494PubMedCrossRefGoogle Scholar
  4. 4.
    Frank SJ (2000) Receptor dimerization in GH and erythropoietin action - it takes two to tango, but how? Endocrinology 143:2–10CrossRefGoogle Scholar
  5. 5.
    Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, Latini R, Xie QW, Smart J, Su-Rick CJ, Pobre E, Diaz D, Gomez D, Hand C, Coleman T, Cerami A (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA 101:14907–14912PubMedCrossRefGoogle Scholar
  6. 6.
    Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF (1999) Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: A direct role for Stat5 in Bcl-X(L) induction. Cell 98:181–191PubMedCrossRefGoogle Scholar
  7. 7.
    Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241PubMedCrossRefGoogle Scholar
  8. 8.
    Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P, Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S, Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A, Brines M (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242PubMedCrossRefGoogle Scholar
  9. 9.
    Westenfelder C, Biddle DL, Baranowski RL (1999) Human, rat, and mouse kidney cells express functional erythropoietin receptors. Kidney Int 55:808–820PubMedCrossRefGoogle Scholar
  10. 10.
    Abdelrahman M, Sharples EJ, McDonald MC, Collin M, Patel NS, Yaqoob MM, Thiemermann C (2004) Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia. Shock 22:63–69PubMedCrossRefGoogle Scholar
  11. 11.
    Bagnis C, Beaufils H, Jacquiaud C, Adabra Y, Jouanneau C, Le Nahour G, Jaudon MC, Bourbouze R, Jacobs C, Deray G (2001) Erythropoietin enhances recovery after cisplatin-induced acute renal failure in the rat. Nephrol Dial Transplant 16:932–938PubMedCrossRefGoogle Scholar
  12. 12.
    Yang CW, Li C, Jung JY, Shin SJ, Choi BS, Lim SW, Sun BK, Kim YS, Kim J, Chang YS, Bang B (2003) Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney. FASEB J 17:1754–1755PubMedCrossRefGoogle Scholar
  13. 13.
    Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, Kieswich J, Allen D, Harwood S, Raftery M, Thiemermann C, Yaqoob MM (2004) Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol 15:2115–2124PubMedCrossRefGoogle Scholar
  14. 14.
    Gong H, Wang W, Kwon TH, Jonassen T, Li C, Ring T, Frøkiær J, Nielsen S (2004) EPO and α-MSH prevent ischemia/reperfusion-induced down-regulation of AQPs and sodium transporters in rat kidney. Kidney Int 66:683–695PubMedCrossRefGoogle Scholar
  15. 15.
    Vesey DA, Cheung C, Pat B, Endre Z, Gobe G, Johnson DW (2004) Erythropoietin protects against ischaemic acute renal injury. Nephrol Dial Transplant 19:348–355PubMedCrossRefGoogle Scholar
  16. 16.
    Patel NS, Sharples EJ, Cuzzocrea S, Chatterjee PK, Britti D, Yaqoob MM, Thiemermann C (2004) Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo. Kidney Int 66:983–989PubMedCrossRefGoogle Scholar
  17. 17.
    Johnson DW, Pat B, Vesey DA, Guan Z, Endre Z, Gobe GC (2006) Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure. Kidney Int 69:1806–1813PubMedCrossRefGoogle Scholar
  18. 18.
    Stohlawetz PJ, Dzirlo L, Hergovich N, Lackner E, Mensik C, Eichler HG, Kabrna E, Geissler K, Jilma B (2000) Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 95:2983–2989PubMedGoogle Scholar
  19. 19.
    Haiden N, Cardona F, Schwindt J, Berger A, Kuhle S, Homoncik M, Jilma-Stohlawetz P, Pollak A, Jilma B (2005) Changes in thrombopoiesis and platelet reactivity in extremely low birth weight infants undergoing erythropoietin therapy for treatment of anaemia of prematurity. Thromb Haemost 93:118–123PubMedGoogle Scholar
  20. 20.
    Bahlmann FH, Song R, Boehm SM, Mengel M, von Wasielewski R, Lindschau C, Kirsch T, de Groot K, Laudeley R, Niemczyk E, Guler F, Menne J, Haller H, Fliser D (2004) Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure. Circulation 100:1006–1012CrossRefGoogle Scholar
  21. 21.
    Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC (2004) Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 66:753–760PubMedCrossRefGoogle Scholar
  22. 22.
    Coleman TR, Westenfelder C, Togel FE, Yang Y, Hu Z, Swenson L, Leuvenink HG, Ploeg RJ, d’Uscio LV, Katusic ZS, Ghezzi P, Zanetti A, Kaushansky K, Fox NE, Cerami A, Brines M (2006) Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci USA 103:5965–5970PubMedCrossRefGoogle Scholar
  23. 23.
    Bahlmann FH, De Groot K, Spandau JM, Landry AL, Hertel B, Duckert T, Boehm SM, Menne J, Haller H, Fliser D (2004) Erythropoietin regulates endothelial progenitor cells. Blood 103:921–926PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2006

Authors and Affiliations

  • Danilo Fliser
    • 1
  • Ferdinand H. Bahlmann
    • 1
  • Hermann Haller
    • 1
  1. 1.Division of Nephrology, Department of Internal MedicineHannover Medical SchoolHannoverGermany

Personalised recommendations