Effects of everolimus on oxidative stress in kidney model of ischemia/reperfusion injury

TY - JOUR

T1 - Effects of everolimus on oxidative stress in kidney model of ischemia/reperfusion injury

AU - Kezic, Aleksandra

AU - Thaiss, Friedrich

AU - Becker, Jan U

AU - Tsui, Tung Y

AU - Bajcetic, Milica

N1 - Copyright © 2013 S. Karger AG, Basel.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - BACKGROUND/AIMS: 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.CONCLUSION: Our data imply that everolimus treatment may decrease cytoprotective capacity in kidneys exposed to IRI due to promoted oxidative/nitrosative stress.

AB - BACKGROUND/AIMS: 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.CONCLUSION: Our data imply that everolimus treatment may decrease cytoprotective capacity in kidneys exposed to IRI due to promoted oxidative/nitrosative stress.

KW - Animals

KW - Catalase

KW - Glutathione

KW - Glutathione Disulfide

KW - Glutathione Peroxidase

KW - Immunosuppressive Agents

KW - Kidney

KW - Mice

KW - Mice, Inbred C57BL

KW - NADP

KW - Oxidative Stress

KW - Reperfusion Injury

KW - Sirolimus

KW - Superoxide Dismutase

U2 - 10.1159/000348496

DO - 10.1159/000348496

M3 - SCORING: Journal article

C2 - 23548777

VL - 37

SP - 291

EP - 301

JO - AM J NEPHROL

JF - AM J NEPHROL

SN - 0250-8095

IS - 4

ER -