title: Effects of everolimus on oxidative stress in kidney model of ischemia/reperfusion injury.
abstract: OBJECTIVE
  Reactive oxygen species play an important role in the pathogenesis of kidney ischemia/reperfusion injury (IRI) which may be influenced by immunosuppressive therapy. Pertinent to this, we investigated the effects of the mTOR inhibitor everolimus on redox settings and the activity of the anti-oxidative system in kidneys exposed to IRI.
  
  
  METHODS
  C57BL/6 mice were subjected to IRI by clamping both renal pedicles for 45 min. Everolimus was applied in daily, subcutaneous doses (0.25 mg/kg body weight), starting 1 day before IRI induction. Both everolimus-treated and non-treated mice were sacrificed at several time points, starting 30 min and finishing 7 days after IRI induction. Markers of oxidation such as glutathione and NADPH levels and anti-oxidative enzyme activities were determined in the kidneys.
  
  
  RESULTS
  In comparison to both sham and non-treated animals, the treatment with everolimus resulted in an increased level of markers of oxidation, including a lower level of glutathione, increased level of oxidized glutathione and reduced level of NADPH. The activity of superoxide dismutase was reduced in both experimental groups, but the effects were less pronounced in everolimus-treated animals. In the early phase of reperfusion, everolimus-treated animals showed higher activity of glutathione reductase in comparison to non-treated animals, whereas the activities of glutathione peroxidase and catalase were generally similar. The treatment with everolimus significantly reduced heme oxygenase-1 expression and increased iNOS mRNA expression when compared to non-treated animals.
  
  
  CONCLUSIONS
  Our data imply that everolimus treatment may decrease cytoprotective capacity in kidneys exposed to IRI due to promoted oxidative/nitrosative stress.
authors.affiliation: School of Medicine, University of Belgrade, Belgrade, Serbia. aleksandrakezic@yahoo.com
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kezic
authors.forename: Friedrich
authors.initials: F
authors.lastname: Thaiss
authors.forename: Jan U
authors.initials: JU
authors.lastname: Becker
authors.forename: Tung Y
authors.initials: TY
authors.lastname: Tsui
authors.forename: Milica
authors.initials: M
authors.lastname: Bajcetic
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D000068338:Everolimus; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide; D005979:Glutathione Peroxidase / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D015427:Reperfusion Injury / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D009249:NADP; D000068338:Everolimus; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D019803:Glutathione Disulfide; D020123:Sirolimus