Pleiotropic Effects of Erythropoietin
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The 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.
AuthorsSharples, Edward John
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