Seminar on Tissue-protective Properties of Erythropoietin

Convener: WS Fred WONG, Assoc. Professor of Pharmacology, YLLSOM, NUHS

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 in response to tissue hypoxia under the control of the oxygen-sensitive transcription factor hypoxia-inducible factor-1 (HIF-1). EPO binds to a preformed EPO receptor homodimer (EPOR)2 present on the cell membrane of erythrocytic progenitors. Upon activation of (EPOR)2 a molecular cascade begins with the phosphorylation of Janus tyrosine kinase 2 that 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. The overall effect is a compensatory adaptation to tissue hypoxia by enhancing the oxygen-carrying capacity of the blood, and thus therapeutically useful for the treatment of anaemia of chronic kidney disease (CKD) and chemotherapy.   In the last decade, several key lines of evidence have strongly supported the view that endogenous EPO may play a crucial role in dampening this excessive tissue injury. Systemic administration of EPO has been found (by us and others) to be active in a large number of animal models associated with IRI including stroke, myocardial infarction, acute kidney injury, haemorrhagic shock  and SIRS. However, several large clinical trials of EPO carried out to assess potential utility of normalizing the marginally low haemoglobin levels of patients with breast or head and neck cancers unexpectedly found an increase in mortality within the EPO arm due to tumour progression or significant thrombosis. Additionally, a surgical trauma trial that showed increased survival in the EPO arm also showed that this was at the expense of a 40% increase in clinically significant thromboses. Thus, although administration of EPO has potentially valuable tissue protective effects, clinical trials have shown EPO administration is accompanied by significant adverse complications. Notably, these complications appear to be more frequent with high doses of EPO, such as used in the tissue protection proof-of-concept trials. There is, therefore, a need for novel EPO analogues that lack erythropoietic activity for the treatment of IRI.