Role of mitochondrial-derived oxidants in renal tubular cell cold-storage injury.
Cold storage (CS) is regarded as a necessary procedure during donation of a deceased-donor kidney that helps to optimize organ viability. Increased oxidant generation during CS as well as during the reperfusion (or rewarming/CS.RW) phase has been suggested to be a major contributor to renal injury, although the source of and/or biochemical pathways involved in oxidant production remain unclear. The purpose of this study was to determine if renal tubular mitochondrial superoxide is capable of inducing oxidant production and mitochondrial damage in response to a CS.RW insult. To test the role of mitochondrial superoxide in CS.RW injury, we used rat renal proximal tubular (NRK) cells overexpressing manganese superoxide dismutase (MnSOD), the major mitochondrial antioxidant. Oxidant production, mitochondrial membrane potential, respiratory complex function, and cell death were all altered after exposure of NRK cells to CS.RW. MnSOD overexpression or inhibition of nitric oxide synthase provided significant protection against oxidant generation, respiratory complex inactivation, and cell death. These findings implicate mitochondrial superoxide, nitric oxide, and their reaction product, peroxynitrite, as key signaling molecules involved in CS.RW injury of renal tubular cells and suggest that therapeutic inhibition of these pathways may protect the donor kidney.
Mitchell
Tanecia
T
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Saba
Hamida
H
Laakman
Joe
J
Parajuli
Nirmala
N
MacMillan-Crow
Lee Ann
LA
D000818:Animals; D002460:Cell Line; D019069:Cell Respiration / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003080:Cold Temperature / Q000009:adverse effects; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009926:Organ Preservation; D016877:Oxidants / Q000378:metabolism; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
D016877:Oxidants; D013481:Superoxides; D013482:Superoxide Dismutase