title: NADPH oxidase 4 deficiency increases tubular cell death during acute ischemic reperfusion injury.
abstract: NADPH oxidase 4 (NOX4) is highly expressed in kidney proximal tubular cells. NOX4 constitutively produces hydrogen peroxide, which may regulate important pro-survival pathways. Renal ischemia reperfusion injury (IRI) is a classical model mimicking human ischemic acute tubular necrosis. We hypothesized that NOX4 plays a protective role in kidney IRI. In wild type (WT) animals subjected to IRI, NOX4 protein expression increased after 24 hours. NOX4 KO (knock-out) and WT littermates mice were subjected to IRI. NOX4 KO mice displayed decreased renal function and more severe tubular apoptosis, decreased Bcl-2 expression and higher histologic damage scores compared to WT. Activation of NRF2 was decreased in NOX4 KO mice in response to IRI. This was related to decreased KEAP1 oxidation leading to decreased NRF2 stabilization. This resulted in decreased glutathione levels. In vitro silencing of NOX4 in cells showed an enhanced propensity to apoptosis, with reduced expression of NRF2, glutathione content and Bcl-2 expression, similar to cells derived from NOX4 KO mice. Overexpression of a constitutively active form of NRF2 (caNRF2) in NOX4 depleted cells rescued most of this phenotype in cultured cells, implying that NRF2 regulation by ROS issued from NOX4 may play an important role in its anti-apoptotic property.
authors.affiliation: Laboratory of Nephrology, Department of Medicine Specialties and PHYM department, University Hospital and University of Geneva, Switzerland.
authors.forename: Stellor
authors.initials: S
authors.lastname: Nlandu-Khodo
authors.affiliation: Laboratory of Nephrology, Department of Medicine Specialties and PHYM department, University Hospital and University of Geneva, Switzerland.
authors.forename: Romain
authors.initials: R
authors.lastname: Dissard
authors.affiliation: Laboratory of Nephrology, Department of Medicine Specialties and PHYM department, University Hospital and University of Geneva, Switzerland.
authors.forename: Udo
authors.initials: U
authors.lastname: Hasler
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Universität Innsbruck, Institute for Biomedical Aging Research, Innsbruck, Austria.
authors.forename: Haymo
authors.initials: H
authors.lastname: Pircher
authors.affiliation: Universität Innsbruck, Institute for Biomedical Aging Research, Innsbruck, Austria.
authors.forename: Pidder
authors.initials: P
authors.lastname: Jansen-Durr
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Switzerland.
authors.forename: Karl Heinz
authors.initials: KH
authors.lastname: Krause
authors.affiliation: Laboratory of Nephrology, Department of Medicine Specialties and PHYM department, University Hospital and University of Geneva, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Martin
authors.affiliation: Laboratory of Nephrology, Department of Medicine Specialties and PHYM department, University Hospital and University of Geneva, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: de Seigneux
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000235:genetics*; D003404:Creatinine / Q000652:urine; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005978:Glutathione / Q000096:biosynthesis; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D000074663:NADPH Oxidase 4 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
chemical_list: D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D003404:Creatinine; D000074663:NADPH Oxidase 4; D005978:Glutathione