Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pathology

Supervisor

Anthony M. Jevnikar

2nd Supervisor

Zhuxu Zhang

Joint Supervisor

Abstract

Renal transplantation invariably results in tissue injury resulting from ischemia reperfusion injury (IRI), inflammation, drug toxicity, and rejection. Tubular epithelial cells (TEC) comprise the majority of renal parenchyma and are susceptible to cell death and injury during diverse forms of inflammation, which has direct and indirect effects on long term allograft function. Renal TEC have the unique ability to attenuate inflammation and alloimmune injury through the expression of various mediators of cell death and inflammatory molecules. Inhibition of cell death pathways in renal allografts may influence outcomes of alloimmune responses and graft survival. In this body of investigation, alteration of apoptosis and necroptosis forms of TEC death in vitro, were tested for their ability to extend allograft survival in vivo. Apoptotic death induced by cytotoxic cells during allograft rejection was inhibited by TEC expression of Granzyme B inhibiting serine protease inhibitor-6 (SPI-6) and prolonged graft survival and function. Apoptosis death of TEC can also be initiated during renal IRI and with rejection by pro-inflammatory cytokines through surface death receptors. However, inhibition of TNFα-induced apoptosis in TEC through caspase-8 upregulated the receptor interacting protein kinase 1 and 3 (RIPK1/3)-mediated necroptosis pathway to limit graft survival. However, inhibition of RIPK1/3 necroptotic death during renal IRI and transplantation was able to preserve renal function and promote long term graft survival. Augmented pro-inflammatory effects following necrotic cell death were related to an increased release of high mobility group box 1 (HMGB1). Use of the HMGB1 inhibitor glycyrrhizic acid (GZA) inhibited inflammatory responses in vitro and was able to ameliorate renal IRI. Collectively these studies highlight the importance of endogenous donor kidney factors in regulating inflammatory cell death and subsequently the severity and outcomes of allograft rejection. Regulators of parenchymal cell death in kidney and other solid organs may provide entirely new therapeutic targets for transplantation which will promote long term allograft survival.

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