NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice

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  • dc.contributor.author Herranz-Itúrbe, Macarena
  • dc.contributor.author López-Luque, Judit
  • dc.contributor.author Gonzalez-Sanchez, Ester
  • dc.contributor.author Caballero-Díaz, Daniel
  • dc.contributor.author Crosas-Molist, Eva
  • dc.contributor.author Martín-Mur, Beatriz
  • dc.contributor.author Gut, Marta
  • dc.contributor.author Esteve-Codina, Anna
  • dc.contributor.author Jaquet, Vincent
  • dc.contributor.author Jiang, Joy X.
  • dc.contributor.author Török, Natalie J.
  • dc.contributor.author Fabregat, Isabel
  • dc.date.accessioned 2021-06-30T10:21:55Z
  • dc.date.available 2021-06-30T10:21:55Z
  • dc.date.issued 2021
  • dc.description.abstract Liver is a unique organ in displaying a reparative and regenerative response after acute/chronic damage or partial hepatectomy, when all the cell types must proliferate to re-establish the liver mass. The NADPH oxidase NOX4 mediates Transforming Growth Factor-beta (TGF-β) actions, including apoptosis in hepatocytes and activation of stellate cells to myofibroblasts. Aim of this work was to analyze the impact of NOX4 in liver regeneration by using two mouse models where Nox4 was deleted: 1) general deletion of Nox4 (NOX4-/-) and 2) hepatocyte-specific deletion of Nox4 (NOX4hepKO). Liver regeneration was analyzed after 2/3 partial hepatectomy (PH). Results indicated an earlier recovery of the liver-to-body weight ratio in both NOX4-/- and NOX4hepKO mice and an increased survival, when compared to corresponding WT mice. The regenerative hepatocellular fat accumulation and the parenchyma organization recovered faster in NOX4 deleted livers. Hepatocyte proliferation, analyzed by Ki67 and phospho-Histone3 immunohistochemistry, was accelerated and increased in NOX4 deleted mice, coincident with an earlier and increased Myc expression. Primary hepatocytes isolated from NOX4 deleted mice showed higher proliferative capacity and increased expression of Myc and different cyclins in response to serum. Transcriptomic analysis through RNA-seq revealed significant changes after PH in NOX4-/- mice and support a relevant role for Myc in a node of regulation of proliferation-related genes. Interestingly, RNA-seq also revealed changes in the expression of genes related to activation of the TGF-β pathway. In fact, levels of active TGF-β1, phosphorylation of Smads and levels of its target p21 were lower at 24 h in NOX4 deleted mice. Nox4 did not appear to be essential for the termination of liver regeneration in vivo, neither for the in vitro hepatocyte response to TGF-β1 in terms of growth inhibition, which suggest its potential as therapeutic target to improve liver regeneration, without adverse effects.
  • dc.description.sponsorship This work was supported by grants from: 1) Agencia Estatal de Investigación and Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (MICINN), Spain, cofounded by FEDER funds/European Regional Development Fund – a way to build Europe- (SAF2015-64149-R and RTI2018-094079-B-I00 to I.F.; PT17/0009/0019 to A.E.-C.; Programa Operativo FEDER: Plurirregional de España (POPE) 2014–2020 and Catalunya 2014–2020 to CNAG-CRG authors; 2) NIH 2R01DK083283 (to N.J.T.). M.H.-I. was recipient of a predoctoral grant from IDIBELL-Oncobell Program. D.C-D. was recipient of a pre-doctoral grant from the FPI program. J.L-L. was recipient of Boehringer Ingelheim Fonds Travel grant. The CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, is funded by the Instituto de Salud Carlos III, Spain. We thank the Generalitat de Catalunya through the CERCA Programme and the Departament de Salut and Departament d’Empresa i Coneixement, the Centro de Excelencia Severo Ochoa and the MICINN to the EMBL partnership for institutional support
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Herranz-Itúrbide M, López-Luque J, Gonzalez Sanchez E, Caballero-Díaz D, Crosas-Molist E, Martín-Mur B, Gut M, Esteve-Codina A et al. NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice. Redox Biol. 2021. 40:101841. DOI: 10.1016/j.redox.2020.101841
  • dc.identifier.doi http://dx.doi.org/10.1016/j.redox.2020.101841
  • dc.identifier.issn 2213-2317
  • dc.identifier.uri http://hdl.handle.net/10230/48026
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.rights © 2020 M. Herranz-Itúrbide et al.Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.other Hepatectomia
  • dc.subject.other Fetge -- Regeneració
  • dc.subject.other NADPH oxidasa
  • dc.title NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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