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Prophylaxis of renal ischaemia reperfusion injury: Ischaemic preconditioning and drug repurposing

Foxwell, David 2023. Prophylaxis of renal ischaemia reperfusion injury: Ischaemic preconditioning and drug repurposing. PhD Thesis, Cardiff University.
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Acute Kidney Injury (AKI) is a devastating condition leading to the morbidity and mortality in millions of sufferers each year. The commonest cause of AKI is ischaemic reperfusion injury (IRI), which often complicates organ transplantation and sepsis. Despite extensive scientific research, no effective preventative treatments are currently available for IRI in humans. In in vivo models, IRI in the rat kidney mimics the functional and histological injury seen in the human kidney following IRI. A preventative treatment for IRI called ischaemic preconditioning (IPC) has, in some instances, been shown to ameliorate IRI in vivo. However, the detailed molecular mechanisms underlying IPC function remain unknown, and this technique has failed to translate to the clinical setting. The purpose of the work carried out in this thesis was to investigate alterations in gene expression profiles caused by IRI, to characterise changes to this IRI-specific gene expression profile resulting from IPC treatment, and to investigate pharmacological agents which could be used to attenuate IRI. The work first used an established in vivo rat model of IRI to optimise a suitable IPC protocol. Next generation sequencing (NGS) was then used to perform an unbiased analysis of the transcriptomic profiles elicited by IRI and IPC. Bioinformatic analysis of IRI revealed enrichment of pathways linked to cytokine dysregulation, nuclear signalling, extra cellular matrix/cytoskeleton signalling and leucocyte trafficking. Two different IPC strategies were compared computationally and were found to act via similar response pathways. Using the transcriptional profile data for IRI and IPC, a pathway-based mapping analysis was used to identify candidate drugs to prevent IRI by recapitulating the effects of IPC. Six drugs were validated in vivo, revealing in particular the beneficial effects of the drug pirfenidone in renal IRI prevention.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 10 May 2024
Last Modified: 10 May 2024 12:49

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