Hydrogen sulfide protects renal grafts against prolonged cold ischemia-reperfusion injury via specific mitochondrial actions
American Journal of Transplantation
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Ischemia-reperfusion injury (IRI) is unavoidably caused by loss and subsequent restoration of blood flow during organ procurement and prolonged IRI results in increased rates of delayed graft function and early graft loss. The endogenously produced gasotransmitter, hydrogen sulfide (H2 S), is a novel molecule that mitigates hypoxic tissue injury. The current study investigates the protective mitochondrial effects of H2 S during in vivo cold storage and subsequent renal transplantation (RTx) and in vitro cold hypoxic renal injury. Donor allografts from Brown Norway rats treated with University of Wisconsin (UW) solution + H2 S (150 μM NaSH) during prolonged (24-hour) cold (4°C) storage exhibited significantly (p<0.05) decreased acute necrotic/apoptotic injury and significantly (p<0.05) improved function and recipient Lewis rat survival compared to UW solution alone. Treatment of rat kidney epithelial cells (NRK-52E) with the mitochondrial-targeted H2 S donor, AP39, during in vitro cold hypoxic injury improved the protective capacity of H2 S >1000-fold compared to similar levels of the non-specific H2 S donor, GYY4137 and also improved syngraft function and survival following prolonged cold storage compared to UW. H2 S treatment mitigates cold IRI-associated renal injury via mitochondrial actions and could represent a novel therapeutic strategy to minimize the detrimental clinical outcomes of prolonged cold IRI during RTx.
This work was supported by grants from Physicians Services Incorporated and the Canadian Urological Association (AS) and by a Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award from the Canadian Institutes of Health Research (IL). MW and MEW would like to thank the Medical Research Council UK (MR/M022706/1) for their generous research support. RT would like to acknowledge the Brian Ridge Scholarship for support.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ajt.14080 This article is protected by copyright. All rights reserved.
Accepted manuscript online: 15 October 2016
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