It is recognised that the most common cause of acute renal failure is ischaemic injury. I have therefore used an animal model to investigate the molecular mechanisms underlying renal cell death and cell regeneration that occur post-ischaemic injury. A number of genetic programmes are activated post-ischaemic renal injury, which mediate a variety of pathways including those leading to cell death and those enabling cell regeneration and repair. I identified the up-regulation of a number of genes following ischaemic renal injury and characterised the temporal and spatial expression of these genes using northern blotting, in-situ hybridisation and immunohistochemistry. Using differential display PCR I detected the up-regulation of calcyclin, a member of the S100 family of EF-hand calcium binding proteins, and propose that calcyclin may play a role in the regenerative phase following ischaemic renal injury. Conversely I report the induced expression of a pro-apoptotic gene, Siva, which may mediate cell death occurring immediately following ischaemia. Further work identified the up-regulation of a cell surface receptor, CD44, and its ligands osteopontin and hyaluronic acid suggesting an important role for CD44 during the recovery phase of ischaemic acute renal failure. The final piece of work in this thesis describes the use of a novel therapeutic strategy to ameliorate the course of ischaemic acute renal failure through the inhibition of the DNA repair enzyme, poly-ADP ribose polymerase (PARP). Excessive activation of PARP exhausts ATP reserves that are essential for cell regeneration following ischaemic injury. The inhibition of PARP preserves ATP levels and allows for a more robust proliferative response.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:409377 |
| Date | January 2003 |
| Creators | Lewington, Andrew James Peter |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/29432 |
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