Erythropoietin (EPO) in acute kidney injury

Elizabeth Moore, Rinaldo Bellomo, Elizabeth Moore, Rinaldo Bellomo

Abstract

Erythropoietin (EPO) is a 30.4 kDa glycoprotein produced by the kidney, and is mostly well-known for its physiological function in regulating red blood cell production in the bone marrow. Accumulating evidence, however, suggests that EPO has additional organ protective effects, which may be useful in the prevention or treatment of acute kidney injury. These protective mechanisms are multifactorial in nature and include inhibition of apoptotic cell death, stimulation of cellular regeneration, inhibition of deleterious pathways, and promotion of recovery.In this article, we review the physiology of EPO, assess previous work that supports the role of EPO as a general tissue protective agent, and explain the mechanisms by which it may achieve this tissue protective effect. We then focus on experimental and clinical data that suggest that EPO has a kidney protective effect.

Figures

Figure 1
Figure 1
The main pathways of the effects of EPO. The intracellular domain of the EPOR contains phosphotyrosines, which are phosphorylated by activation of a member of the Janus-type protein tyrosine kinase family (JAK2) bound to the EPOR. These phosphotyrosines serve as docking sites for signal transducer and activator of transcription 5 (STAT5) and activate the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) pathway. Akt stimulates IKK to phosphorylate, which phosphorylates the inhibitory IkB protein causing it to dissociate from NF-kB, which causes its activation (Modified from Anaesth Intensive Care 2011, in press).
Figure 2
Figure 2
Apoptotic pathways influenced by EPO. Activated STAT5 promotes transcription of promitogenic and antiapoptotic genes associated with apoptotic regulation and cytoprotection. Akt promotes cell survival and antiapoptotic effects by 1) inhibiting forkhead transcription factor (FOXO3a), a trigger for apoptosis; 2) inactivating glycogen synthase kinase 3β (GSK3β), thus preventing cell injury; 3) reducing the activity of proapoptotic proteins Bad and Bax; 4) increasing the activity of antiapoptotic protein Bcl-2; 5) preventing cytochrome C release. NF-kB prevents apoptosis by 1) inducing expression of the inhibitors of apoptotic protein (inh. AP 1&2) and the x-chromosome-linked IAP (X-InhAP), which inhibits caspase 3, 7, and 9; 2) promoting induction of growth arrest and DNA damage protein (Gadd45β), which is associated with cell cycle and DNA repair and suppression of apoptosis; and 3) by activating Bcl-xL. EPO induces heat shock protein 70 (HSP70), which inhibits AIF moving into the nucleus, thus avoiding DNA fragmentation and apoptosis. HSP70 also prevents Apaf-1/cytochrome C (Cyto-C) binding, a complex involved in proapoptotic caspase activation. NB: the + sign indicates activation and the - sign indicates inhibition. (Modified from Anaesth Intensive Care 2011, in press).

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