PhDThe haematopoietic growth factor Erythropoietin (EPO) is essential for the survival of
erythroid progenitors to maturation and differentiation. It has been recognised that the EPO
signalling pathway is also present in other tissues including the brain and vasculature, and is
integral to the physiological response to ischaemia. Exogenous EPO was found to improve
the outcome in animal models of stroke. The primary aim of this thesis was to examine
whether erythropoietin was protective in a model of acute kidney injury, and to determine
the mechanism by which EPO exerted this effect. In vitro experiments using HK-2 cells, a
human tubular epithelial cell line, showed that EPO induced dose-dependent changes in cell
number, and activated a number of intra-cellular signalling pathways. EPO reduced
apoptotic cell death induced by nutrient starvation through the expression of anti-apoptotic
proteins. A short-term model of ischaemia reperfusion was used to determine that EPO
reduced the development of acute kidney injury, with a reduction in caspase activity and
apoptosis. Longer models of ischaemia were then performed to confirm these findings, and
showed that a pre-conditioning regime before the onset of the insult was also effective. In
order to examine the mechanism of action, EPO was used in a model of cisplatin-induced
kidney injury. EPO reduced apoptosis and caspase activation through the maintenance of
mitochondrial membrane potential, inhibition of stress kinase signalling, and expression of
XIAP and Bcl-XL. EPO also reduced the induction of oxidative stress and PARP-1 activity.
EPO was then given to animals exposed to cisplatin and confirmed the finding that pretreatment
with EPO significantly reduced cisplatin nephrotoxicity. Finally, EPO was used in
a model of myocardial infarction and heart cells in culture to confirm that EPO plays a
significant physiological role in cellular protection in multiple tissues