NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice
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 apoptosi...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/175426 |
| Acceso en línea: | https://hdl.handle.net/2445/175426 |
| Access Level: | acceso abierto |
| Palabra clave: | Malalties del fetge Hepatectomia Ratolins (Animals de laboratori) Liver diseases Hepatectomy Mice (Laboratory animals) |
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NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in miceHerranz Itúrbide, MacarenaLópez Luque, JuditGonzález Sánchez, EsterCaballero Díaz, DanielCrosas Molist, EvaMartín Mur, BeatrizGut, M.Esteve Codina, AnnaJaquet, V.Jiang, J. X.Török, N. J.Fabregat Romero, IsabelMalalties del fetgeHepatectomiaRatolins (Animals de laboratori)Liver diseasesHepatectomyMice (Laboratory animals)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.Elsevier B. V.2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/175426Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.redox.2020.101841Redox Biology, 2021, vol. 40https://doi.org/10.1016/j.redox.2020.101841cc by-nc-nd (c) Herranz Itúrbide et al., 2020http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1754262026-05-27T06:46:51Z |
| dc.title.none.fl_str_mv |
NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice |
| title |
NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice |
| spellingShingle |
NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice Herranz Itúrbide, Macarena Malalties del fetge Hepatectomia Ratolins (Animals de laboratori) Liver diseases Hepatectomy Mice (Laboratory animals) |
| title_short |
NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice |
| title_full |
NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice |
| title_fullStr |
NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice |
| title_full_unstemmed |
NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice |
| title_sort |
NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice |
| dc.creator.none.fl_str_mv |
Herranz Itúrbide, Macarena López Luque, Judit González Sánchez, Ester Caballero Díaz, Daniel Crosas Molist, Eva Martín Mur, Beatriz Gut, M. Esteve Codina, Anna Jaquet, V. Jiang, J. X. Török, N. J. Fabregat Romero, Isabel |
| author |
Herranz Itúrbide, Macarena |
| author_facet |
Herranz Itúrbide, Macarena López Luque, Judit González Sánchez, Ester Caballero Díaz, Daniel Crosas Molist, Eva Martín Mur, Beatriz Gut, M. Esteve Codina, Anna Jaquet, V. Jiang, J. X. Török, N. J. Fabregat Romero, Isabel |
| author_role |
author |
| author2 |
López Luque, Judit González Sánchez, Ester Caballero Díaz, Daniel Crosas Molist, Eva Martín Mur, Beatriz Gut, M. Esteve Codina, Anna Jaquet, V. Jiang, J. X. Török, N. J. Fabregat Romero, Isabel |
| author2_role |
author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Malalties del fetge Hepatectomia Ratolins (Animals de laboratori) Liver diseases Hepatectomy Mice (Laboratory animals) |
| topic |
Malalties del fetge Hepatectomia Ratolins (Animals de laboratori) Liver diseases Hepatectomy Mice (Laboratory animals) |
| description |
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. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/175426 |
| url |
https://hdl.handle.net/2445/175426 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.1016/j.redox.2020.101841 Redox Biology, 2021, vol. 40 https://doi.org/10.1016/j.redox.2020.101841 |
| dc.rights.none.fl_str_mv |
cc by-nc-nd (c) Herranz Itúrbide et al., 2020 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc by-nc-nd (c) Herranz Itúrbide et al., 2020 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ |
| eu_rights_str_mv |
openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier B. V. |
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Elsevier B. V. |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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