The majority of kidneys utilized for transplantation are obtained from deceased donors. These kidneys must undergo cold preservation/storage prior to transplantation to preserve tissue viability and to allow time for recipient selection and transport. However, cold storage (CS) can result in tissue injury, kidney discardment, or long-term renal dysfunction following transplantation. The precise biochemical mechanisms responsible for CS and reperfusion (or rewarming, RW) injury remains unclear; however, several studies have implicated a role for increased oxidant generation. Hence, we hypothesize that renal injury in response to CS is caused by increases in superoxide production and mitochondrial dysfunction, and that mitoquinone (MitoQ), a mitochondrial targeted antioxidant, will be able to attenuate renal injury by decreasing superoxide production. The first aim of this project was to investigate the source of oxidant generation using normal rat kidney (NRK) proximal tubular cells. Findings from these studies implicate mitochondrial superoxide, nitric oxide, and their reaction product, peroxynitrite, as key signaling molecules involved in CS.RW injury of NRK cells and suggest that therapeutic inhibition of these pathways may protect the donor kidney. Subsequently, the second aim of this project was to test whether adding MitoQ to University of Wisconsin cold preservation solution could ameliorate CS injury in NRK cells and isolated rat kidneys. MitoQ decreased CS injury significantly and should be evaluated further in a larger animal CS model and its effect on renal function following transplantation. The final aim of this project was to use a non-heart beating donor (NHBD) model to evaluate the effect of CS on this type of donor kidney. Manganese superoxide dismutase (MnSOD) was inactivated in the NHBD kidney and was reversed with CS. The cause of MnSOD inactivation is not clear, but appears to be due to a post-translational modification and will be the focus of future studies in the laboratory. Together, our studies strongly implicate the central involvement of mitochondrial superoxide in the development of CS-mediated injury. Exploring these avenues further could provide healthier kidneys from deceased donors, decrease the number of kidneys discarded, and/or offer improved renal function and enhanced quality of life for transplant recipients.
|Advisor:||MacMillan-Crow, Lee Ann|
|Commitee:||Abul-Ezz, Sameh R., Crow, John P., Price, Peter M., Rusch, Nancy J.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 72/08, Dissertation Abstracts International|
|Subjects:||Cellular biology, Pharmacology, Physiology|
|Keywords:||Cold storage, Kidney, Mitochondria, Mitoquinone, Oxidants, Renal injury, Transplantation|
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