Erythropoietin (EPO) is used at present in clinical practice to stimulate red cell production. However, a number of reports have emerged suggesting the presence of nonerythropoietic properties for EPO. Chief among them is its ability to confer protection against acute tissue injury. In this report, we briefly review the role of EPO in tissue protection and provide examples of tissue protection using cisplatin-induced kidney injury model. Also provided is a brief description of potential pathways through which EPO may be mediating this effect.
SirenAL, FratelliM, BrinesM, . Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A. 2001;98:4044–4049.
2.
JunkAK, MammisA, SavitzSI, . Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2002;99:10659–10664.
3.
YangCW, LiC, JungJY, . Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney. FASEB J. 2003;17:1754–1755.
4.
CalvilloL, LatiniR, KajsturaJ, . Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A. 2003;100:4802–4806.
5.
ErbayraktarS, GrassoG, SfacteriaA, . Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci U S A. 2003;100:6741–6746.
VaziriND, ZhouXJ, LiaoSY.Erythropoietin enhances recovery from cisplatin-induced acute renal failure. Am J Physiol. 1994;266:F360–F366.
8.
SalahudeenAK, HaiderN, JenkinsJ, . Antiapoptotic properties of erythropoiesis-stimulating proteins in models of cisplatin-induced acute kidney injury. Am J Physiol Renal Physiol. 2008;294:F1354–F1365.
9.
SalahudeenA, PoovalaV, ParryW, . Cisplatin induces N-acetyl cysteine suppressible F2-isoprostane production and injury in renal tubular epithelial cells. J Am Soc Nephrol. 1998;9:1448–1455.
10.
BittorfT, SeilerJ, LudtkeB, . Activation of STAT5 during EPO-directed suppression of apoptosis. Cell Signal. 2000;12:23–30.
11.
BaoH, Jacobs-HelberSM, LawsonAE, . Protein kinase B (c-Akt), phosphatidylinositol 3-kinase, and STAT5 are activated by erythropoietin (EPO) in HCD57 erythroid cells but are constitutively active in an EPO-independent, apoptosis-resistant subclone (HCD57-SREI cells). Blood. 1999;93:3757–3773.
12.
CorwinHL, GettingerA, FabianTC, . Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357:965–976.
13.
ColemanT, BrinesM.Recombinant human erythropoietin in critical illness: a role beyond anemia?Crit Care. 2004;8:337–341.
14.
MaieseK, LiF, ChongZZ.New avenues of exploration for erythropoietin. JAMA. 2005;293:90–95.
15.
JubinskyPT, KrijanovskiOI, NathanDG, . The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor. Blood. 1997;90(5):1867–1873.
16.
HandCC, BrinesM.Promises and pitfalls in erythropoietin-mediated tissue protection: are nonerythropoietic derivatives a way forward?J Investig Med. 2011;59:1073–1082.
17.
WojchowskiDM, GregoryRC, MillerCP, . Signal transduction in the erythropoietin receptor system. Exp Cell Res. 1999;253(1):143–156.
18.
AgellN, BachsO, RocamoraN, . Modulation of the Ras/Raf/MEK/ERK pathway by Ca(2+), and calmodulin. Cell Signal. 2002;14(8):649–654.
BrinesM.The therapeutic potential of erythropoiesis-stimulating agents for tissue protection: a tale of two receptors. Blood Purif. 2010;29:86–92.
21.
BrinesM, PatelNS, VillaP, . Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008;105:10925–10930.
