title: Using an Integrated -Omics Approach to Identify Key Cellular Processes That Are Disturbed in the Kidney After Brain Death.
abstract: In an era where we are becoming more reliant on vulnerable kidneys for transplantation from older donors, there is an urgent need to understand how brain death leads to kidney dysfunction and, hence, how this can be prevented. Using a rodent model of hemorrhagic stroke and next-generation proteomic and metabolomic technologies, we aimed to delineate which key cellular processes are perturbed in the kidney after brain death. Pathway analysis of the proteomic signature of kidneys from brain-dead donors revealed large-scale changes in mitochondrial proteins that were associated with altered mitochondrial activity and morphological evidence of mitochondrial injury. We identified an increase in a number of glycolytic proteins and lactate production, suggesting a shift toward anaerobic metabolism. Higher amounts of succinate were found in the brain death group, in conjunction with increased markers of oxidative stress. We characterized the responsiveness of hypoxia inducible factors and found this correlated with post-brain death mean arterial pressures. Brain death leads to metabolic disturbances in the kidney and alterations in mitochondrial function and reactive oxygen species generation. This metabolic disturbance and alteration in mitochondrial function may lead to further cellular injury. Conditioning the brain-dead organ donor by altering metabolism could be a novel approach to ameliorate this brain death-induced kidney injury.
authors.affiliation: Centre for Cellular and Molecular Physiology, Oxford University, Oxford, UK.|Oxford Transplant Centre, Nuffield Department of Surgical Sciences, Churchill Hospital, Oxford, UK.
authors.forename: M Z
authors.initials: MZ
authors.lastname: Akhtar
authors.affiliation: Oxford Transplant Centre, Nuffield Department of Surgical Sciences, Churchill Hospital, Oxford, UK.|Target Discovery Institute, Oxford University, Oxford, UK.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Oxford Transplant Centre, Nuffield Department of Surgical Sciences, Churchill Hospital, Oxford, UK.|Target Discovery Institute, Oxford University, Oxford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Kaisar
authors.affiliation: Centre for Cellular and Molecular Physiology, Oxford University, Oxford, UK.|Oxford Transplant Centre, Nuffield Department of Surgical Sciences, Churchill Hospital, Oxford, UK.
authors.forename: M L
authors.initials: ML
authors.lastname: Lo Faro
authors.affiliation: Surgical Research Laboratory, University of Groningen, Groningen, the Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Rebolledo
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
authors.forename: K
authors.initials: K
authors.lastname: Morten
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: L C
authors.initials: LC
authors.lastname: Heather
authors.affiliation: Department of Surgery, Imperial College, London, UK.|Kolling Institute for Medical Research, The University of Sydney, New South Wales, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Dona
authors.affiliation: Surgical Research Laboratory, University of Groningen, Groningen, the Netherlands.
authors.forename: H G
authors.initials: HG
authors.lastname: Leuvenink
authors.affiliation: Oxford Transplant Centre, Nuffield Department of Surgical Sciences, Churchill Hospital, Oxford, UK.
authors.forename: S V
authors.initials: SV
authors.lastname: Fuggle
authors.affiliation: Target Discovery Institute, Oxford University, Oxford, UK.
authors.forename: B M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: Centre for Cellular and Molecular Physiology, Oxford University, Oxford, UK.
authors.forename: C W
authors.initials: CW
authors.lastname: Pugh
authors.affiliation: Oxford Transplant Centre, Nuffield Department of Surgical Sciences, Churchill Hospital, Oxford, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Ploeg
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D001926:Brain Death / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D018384:Oxidative Stress / Q000235:genetics*; D040901:Proteomics / Q000379:methods*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction
chemical_list: D015415:Biomarkers