Abstract: SA-PO064
Drug Repurposing for the Prophylaxis of Renal Ischaemia Reperfusion Injury
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Foxwell, David A., Wales Kidney Research Unit (WKRU), Cardiff, CARDIFF, United Kingdom
- Khalid, Usman, Cardiff Transplant Unit, Cardiff, United Kingdom
- Pino-Chavez, Gilda, Cardiff University, Cardiff, United Kingdom
- Chavez, Rafael E., University Hospital of Wales, Cardiff, United Kingdom
- Bowen, Timothy, Cardiff University, Cardiff, United Kingdom
- Fraser, Donald, Cardiff University, Cardiff, United Kingdom
Background
Ischaemic Preconditioning applied to the kidney (direct IPC) or to distant sites (indirect IPC) confers protection from subsequent ischemic Acute Kidney Injury (AKI). However, IPC has not proven effective in clinical trials enrolling individuals at high AKI risk. The purpose of this study was to employ a drug repurposing approach, in an attempt to translate the experimental benefit of IPC into candidate agents for clinical testing.
Methods
IPC regimens were tested iteratively in a rat model of bilateral IRI. Optimised direct and indirect IPC approaches were transcriptomically profiled by RNA sequencing, and a shared protective signature identified. Computational prediction of drug repurposing candidates was performed by Ingenuity Pathway Analysis. Effects of predicted candidates were evaluated in vivo, by renal histology and serum creatinine.
Results
Optimum benefit was observed with direct and indirect pulsatile IPC employing two minutes of ischaemia followed by five minutes of reperfusion, repeated for 3 cycles. Whole kidney transcriptomic profiling performed across sham, IRI, and direct- and indirect-IPC/IRI groups (n=6 per group) mapped to 16,780 unique genes, of which 2,193 genes were differentially expressed between IRI and sham, which IPA attributed to a phenotype of Acute Renal Failure (p = 1.32 x 10-27) and Renal Proximal Tubular Toxicity (p = 5.06 x 10-15). A core set of master regulators and pathways were identified within inflammatory response, oxidative stress and cell cycle, that were diminished by direct and indirect IPC. Comparison with transcriptomic information available for 23,686 biological drugs and chemicals (compounds) contained within the IPA knowledge base was employed to identify repurposing candidates for benefit in IRI prophylaxis. Six compounds exhibiting favourable characteristics for progression to clinical testing were further evaluated in vivo, and all exhibited functional benefits when administered as a single dose prophylaxis pre-IRI.
Conclusion
Our data identify a common protective gene expression signature between direct and indirect IPC. These findings provide novel insights into the pathology of IRI injury and protection afforded by IPC. Computational transcriptional analysis using this dataset has identified candidate drugs for repurposing.