caa a22 4500 530098318 20181217030326.0 cr unu---uuuuu 181026e20161207xx s 000 0 eng 10.3929/ethz-b-000124175 doi 10.1038/srep38598 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/124175 NADPH oxidase 4 deficiency increases tubular cell death during acute ischemic reperfusion injury [Elektronische Daten] [Stellor Nlandu-Khodo, Romain Dissard, Udo Hasler, Matthias Schäfer, Haymo Pircher, Pidder Jansen-Durr, Karl H. Krause, Pierre-Yves Martin, Sophie De Seigneux] Sci Rep Open access ethresearch 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. Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 ethresearch Cell death ethresearch Kidney ethresearch Nlandu-Khodo Stellor joint author Dissard Romain joint author Hasler Udo joint author Schäfer Matthias joint author Pircher Haymo joint author Jansen-Durr Pidder joint author Krause Karl H. joint author Martin Pierre-Yves joint author De Seigneux Sophie joint author Scientific Reports London : Nature Publishing Group 6, p. 38598 2045-2322 http://hdl.handle.net/20.500.11850/124175 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/124175 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Nlandu-Khodo Stellor joint author ETHRESEARCH 700 1- Dissard Romain joint author ETHRESEARCH 700 1- Hasler Udo joint author ETHRESEARCH 700 1- Schäfer Matthias joint author ETHRESEARCH 700 1- Pircher Haymo joint author ETHRESEARCH 700 1- Jansen-Durr Pidder joint author ETHRESEARCH 700 1- Krause Karl H. joint author ETHRESEARCH 700 1- Martin Pierre-Yves joint author ETHRESEARCH 700 1- De Seigneux Sophie joint author ETHRESEARCH 773 0- Scientific Reports London : Nature Publishing Group 6, p. 38598 2045-2322 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access