Protection of NAD(P)H:quinone oxidoreductase 1 against renal ischemia/reperfusion injury in mice |
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Affiliation: | 1. Department of Plastic, Reconstructive and Hand Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland;2. Department of Plastic and Reconstructive Surgery, Turku University Hospital, Finland;3. Department of Thoracic Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland;4. Department of Visceral Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland |
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Abstract: | Ischemia/reperfusion (I/R) is the most common cause of acute renal injury. I/R-induced reactive oxygen species (ROS) are thought to be a major factor in the development of acute renal injury by promoting the initial tubular damage. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a well-known antioxidant protein that regulates ROS generation. The purpose of this study was to investigate whether NQO1 modulates the renal I/R injury (IRI) associated with NADPH oxidase (NOX)-derived ROS production in an animal model. We analyzed renal function, oxidative stress, and tubular apoptosis after IRI. NQO1−/− mice showed increased blood urea nitrogen and creatinine levels, tubular damage, oxidative stress, and apoptosis. In the kidneys of NQO1−/− mice, the cellular NADPH/NADP+ ratio was significantly higher and NOX activity was markedly higher than in those of NQO1+/+ mice. The activation of NQO1 by β-lapachone (βL) significantly improved renal dysfunction and reduced tubular cell damage, oxidative stress, and apoptosis by renal I/R. Moreover, the βL treatment significantly lowered the cellular NADPH/NADP+ ratio and dramatically reduced NOX activity in the kidneys after IRI. From these results, it was concluded that NQO1 has a protective role against renal injury induced by I/R and that this effect appears to be mediated by decreased NOX activity via cellular NADPH/NADP+ modulation. These results provide convincing evidence that NQO1 activation might be beneficial for ameliorating renal injury induced by I/R. |
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Keywords: | Ischemia/reperfusion injury NQO1 NADPH oxidase β-Lapachone Free radicals |
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