title: Role of reduced manganese superoxide dismutase in ischemia-reperfusion injury: a possible trigger for autophagy and mitochondrial biogenesis?
abstract: Excessive generation of superoxide and mitochondrial dysfunction has been described as being important events during ischemia-reperfusion (I/R) injury. Our laboratory has demonstrated that manganese superoxide dismutase (MnSOD), a major mitochondrial antioxidant that eliminates superoxide, is inactivated during renal transplantation and renal I/R and precedes development of renal failure. We hypothesized that MnSOD knockdown in the kidney augments renal damage during renal I/R. Using newly characterized kidney-specific MnSOD knockout (KO) mice the extent of renal damage and oxidant production after I/R was evaluated. These KO mice (without I/R) exhibited low expression and activity of MnSOD in the distal nephrons, had altered renal morphology, increased oxidant production, but surprisingly showed no alteration in renal function. After I/R the MnSOD KO mice showed similar levels of injury to the distal nephrons when compared with wild-type mice. Moreover, renal function, MnSOD activity, and tubular cell death were not significantly altered between the two genotypes after I/R. Interestingly, MnSOD KO alone increased autophagosome formation, mitochondrial biogenesis, and DNA replication/repair within the distal nephrons. These findings suggest that the chronic oxidative stress as a result of MnSOD knockdown induced multiple coordinated cell survival signals including autophagy and mitochondrial biogenesis, which protected the kidney against the acute oxidative stress following I/R.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. lmcrow@uams.edu
authors.forename: Nirmala
authors.initials: N
authors.lastname: Parajuli
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: MacMillan-Crow
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D049109:Cell Proliferation; D004260:DNA Repair / Q000502:physiology; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D063269:Mitochondrial Turnover / Q000502:physiology*; D023421:Models, Animal; D009399:Nephrons / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C002744:3-nitrotyrosine; D014443:Tyrosine; D013482:Superoxide Dismutase