A molecular signature for delayed graft function

McGuinness, D. et al. (2018) A molecular signature for delayed graft function. Aging Cell, 17(5), e12825. (doi: 10.1111/acel.12825) (PMID:30094915) (PMCID:PMC6156499)

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Chronic kidney disease and associated co-morbidities (diabetes, cardiovascular diseases) manifest with an accelerated ageing phenotype, leading ultimately to organ failure and renal replacement therapy. This process can be modulated by epigenetic and environmental factors and promote loss of physiological function and resilience to stress earlier, linking biological age with adverse outcomes post-transplantation including Delayed Graft Function (DGF). The molecular features underpinning this have yet to be fully elucidated. We have determined a molecular signature for loss of resilience and impaired physiological function, via a synchronous genome, transcriptome and proteome snapshot, using human renal allografts as a source of healthy tissue for in vivo model of ageing in humans. This comprises 42 specific transcripts, related through IFNγ signalling, which in allografts displaying clinically impaired physiological function (DGF) exhibited a greater magnitude of change in transcriptional amplitude and elevated expression of non-coding RNAs and pseudogenes, consistent with increased allostatic load. This was accompanied by increased DNA methylation within the promoter and intragenic regions of the DGF panel in pre-perfusion allografts with Immediate Graft Function (IGF) Pathway analysis indicated that an inability to sufficiently resolve inflammatory responses was enabled by decreased resilience to stress and resulted in impaired physiological function in biologically older allografts. Cross-comparison with publically available data sets for renal pathologies identified significant transcriptional commonality for over 20 DGF transcripts. Our data are clinically relevant and important, as they provide a clear molecular signature for the burden of ‘wear and tear’ within the kidney and thus age related physiological capability and resilience.

Item Type:Articles
Additional Information:This research was funded via a collaborative research award from GlaxoSmithKline to PGS.
Glasgow Author(s) Enlighten ID:Monaghan, Miss Laura and Shapter, Oliver and Mohammed, Dr Suhaib and Coley, Dr Shana and Shiels, Professor Paul and Kingsmore, Prof David and McGuinness, Dr Dagmara
Authors: McGuinness, D., Mohammed, S., Monaghan, L., Wilson, P. A., Kingsmore, D. B., Shapter, O., Stevenson, K. S., Coley, S. M., Devey, L., Kirkpatrick, R. B., and Shiels, P. G.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Aging Cell
ISSN (Online):1474-9726
Published Online:09 August 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Aging Cell 17(5): e12825
Publisher Policy:Reproduced under a Creative Commons License

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