title: Nox2 is a mediator of ischemia reperfusion injury.
abstract: Delayed graft function (DGF) results from ischemia-reperfusion injury (IRI) and the generation of reactive oxygen species. We hypothesized that NADPH oxidase 2 (Nox2) plays an important role in pathways leading to DGF. We tested this hypothesis in vitro, in an animal model of IRI using wild type and Nox2(-/-) mice, and in patients with DGF. Under hypoxic conditions, primary tubular epithelial cells from Nox2(-/-) mice had reduced expression of MMP2, vimentin, and HSP27. BUN and creatinine levels were significantly increased in both Nox2(-/-) and WT mice at 4 weeks and 6 months after IRI, suggesting the development of acute and chronic kidney injury. At 4 weeks, kidney fibrosis (α-SMA, picrosirius) and oxidative stress (dihydroethidine, HNE) were significantly reduced in Nox2(-/-) mice, confirming the oxidative and pro-fibrotic effects of Nox2. The molecular signature of IRI using genomic analyses demonstrated a significant decline in hypoxia reponse, oxidative stress, fibrosis, and inflammation in Nox2(-/-) mice. Immunohistochemical analyses of pre-implanatation kidney allograft biopsies from patients with subsequent DGF showed significantly greater Nox2 levels and vascular injury compared with patients without DGF. These studies demonstrate that Nox2 is a modulator of IRI and its absence is associated with reduced inflammation, OS, and fibrosis.
authors.affiliation: School of Medicine and Public Health, University of Wisconsin, Madison, WI.
authors.forename: A S
authors.initials: AS
authors.lastname: Karim
authors.affiliation: Division of Nephrology, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: S R
authors.initials: SR
authors.lastname: Reese
authors.affiliation: Division of Nephrology, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: N A
authors.initials: NA
authors.lastname: Wilson
authors.affiliation: Division of Nephrology, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: L M
authors.initials: LM
authors.lastname: Jacobson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI.
authors.forename: W
authors.initials: W
authors.lastname: Zhong
authors.affiliation: School of Medicine and Public Health, University of Wisconsin, Madison, WI.|Division of Nephrology, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: A
authors.initials: A
authors.lastname: Djamali
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D051799:Delayed Graft Function / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009392:Nephrectomy / Q000009:adverse effects / Q000379:methods; D018384:Oxidative Stress / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism*; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D018709:Statistics, Nonparametric
chemical_list: D015415:Biomarkers; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: animal models: murine; kidney (allograft) function/dysfunction