Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

Dr. Alp Sener

Abstract

Ischemia/reperfusion injury (IRI) is inherent to renal transplantation (RTx) and is initiated when blood supply is necessarily removed during organ procurement (ischemia) and subsequently restored upon engraftment (reperfusion). During renal ischemia, ATP depletion causes tubular epithelial cell (TEC) injury and subsequent release of pro-inflammatory mediators. Upon reperfusion, influx of O2 causes reactive oxygen species (ROS) production and infiltration of innate immune cells which release damaging ROS and proteases. Prolonged periods of IRI are associated with increased risk of delayed graft function (DGF) and decreased long-term graft survival. The endogenously produced gasotransmitter, hydrogen sulfide (H2S), has recently been shown to mediate cytoprotection against ischemic tissue injury. Our investigation examines whether addition of H2S to standard organ preservation solution can better mitigate IRI associated with prolonged cold storage. We have demonstrated that addition of H2S to University of Wisconsin (UW) preservation solution significantly improves early graft function and survival following both moderate (6-hour) and prolonged (24-hour) cold storage during syngeneic (genetically identical) and allogeneic (genetically dissimilar) murine RTx. H2S treatment significantly reduced acute expression of renal injury markers compared to UW, but did not alter progression of allograft rejection. Targeting H2S release to mitochondria improved the potency of H2S-mediated renoprotection >1000 fold during both in vitro and in vivo cold hypoxic/ischemic injury. Our studies provide a strong base of evidence that H2S treatment improves the protective capacity of standard organ preservation solution during both moderate and prolonged cold storage and could diminish the detrimental outcomes of prolonged cold IRI during clinical RTx.

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