The role of microRNAs and ischaemic preconditioning in kidney ischaemia reperfusion injury

• Main Author: Khalid, Usman
• Published: Cardiff University 2016
• Subjects: 616.6; R Medicine (General)
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.699358

Successful kidney transplantation transforms outcome for patients with end stage kidney disease. Delayed graft function (DGF) following Ischaemia Reperfusion Injury (IRI) is a major problem, is hard to predict or monitor, and preventative or therapeutic strategies are lacking. Ischaemic Preconditioning (IPC) may limit IRI, but results are variable and potential mechanisms are not well defined. The aims of this thesis were to study the role of microRNAs, which are post-transcriptional regulators of gene expression vital in many physiological and pathophysiological processes, in the context of IRI, IPC and DGF. An in vivo model of IRI and IPC was developed, and histological, biochemical and mRNA kidney injury marker analyses were undertaken. MicroRNAs were then profiled using both Next Generation Sequencing (NGS) and hybridisation arrays, and changes in selected microRNAs confirmed by RTqPCR. Histology scores, serum creatinine and expression of kidney injury markers were significantly reduced in IPC compared with IRI. Microarray and NGS analysis identified a highly reproducible IRI signature, which was attenuated by IPC. Subsequently, microRNAs were profiled using Taqman Low Density Array (TLDA) and validated by RT-qPCR, from urine samples of kidney transplant patients with and without DGF. A DGF microRNA profile was uncovered, with overlap to the results from the IRI model. These data have identified a microRNA signature of IRI that was attenuated by IPC, which also improved outcome. Urinary microRNAs also showed a promising capability to predict DGF in human kidney transplantation. MicroRNAs thus show significant promise as biomarkers and potential therapeutic targets in this context.