Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress

DSpace/Manakin Repository

Show simple item record

dc.creator Toledo, Flavia D.
dc.creator Basiglio, Cecilia Lorena
dc.creator Barosso, Ismael R.
dc.creator Boaglio, Andrea C.
dc.creator Zucchetti, Andrés E.
dc.creator Sanchez Pozzi, Enrique J.
dc.creator Roma, Marcelo G.
dc.date.accessioned 2019-02-08T23:01:56Z
dc.date.available 2019-02-08T23:01:56Z
dc.date.issued 2017-06
dc.identifier.issn 0340-5761 es
dc.identifier.uri http://hdl.handle.net/2133/13924
dc.description In previous studies, we showed that the pro-oxidant model agent tert-butyl hydroperoxide (tBuOOH) induces alterations in hepatocanalicular secretory function by activating Ca2+-dependent protein kinase C isoforms (cPKC), via F-actin disorganization followed by endocytic internalization of canalicular transporters relevant to bile formation (Mrp2, Bsep). Since mitogen-activated protein kinases (MAPKs) may be downstream effectors of cPKC, we investigated here the involvement of the MAPKs of the ERK1/2, JNK1/2, and p38MAPK types in these deleterious effects. tBuOOH (100 µM, 15 min) increased the proportion of the active, phosphorylated forms of ERK1/2, JNK1/2, and p38MAPK, and panspecific PKC inhibition with bisindolylmaleimide-1 (100 nM) or selective cPKC inhibition with Gö6976 (1 μM) prevented the latter two events. In isolated rat hepatocyte couplets, tBuOOH (100 µM, 15 min) decreased the canalicular vacuolar accumulation of the fluorescent Bsep and Mrp2 substrates, cholylglycylamido fluorescein, and glutathione-methylfluorescein, respectively, and selective inhibitors of ERK1/2 (PD098059), JNK1/2 (SP600125), and p38MAPK (SB203580) partially prevented these alterations. In in situ perfused rat livers, these three MAPK inhibitors prevented tBuOOH (75 µM)-induced impairment of bile flow and the decrease in the biliary output of the Bsep and Mrp2 substrates, taurocholate, and dinitrophenyl-S-glutathione, respectively. The changes in Bsep/Mrp2 and F-actin localization induced by tBuOOH, as assessed by (immuno)fluorescence staining followed by analysis of confocal images, were prevented total or partially by the MAPK inhibitors. We concluded that MAPKs of the ERK1/2, JNK1/2, and p38MAPK types are all involved in cholestasis induced by oxidative stress, by promoting F-actin rearrangement and further endocytic internalization of canalicular transporters critical for bile formation. es
dc.description.sponsorship Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) es
dc.description.sponsorship Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) es
dc.format application/pdf
dc.format.extent 2391 - 2403 es
dc.language.iso eng es
dc.publisher Springer es
dc.rights openAccess es
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/ *
dc.subject Oxidative stress es
dc.subject Hepatocellular cholestasis es
dc.subject Canalicular transporters es
dc.subject Mitogen-activated protein kinases es
dc.subject Actin cytoskeleton es
dc.title Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress es
dc.type article
dc.type artículo
dc.type publishedVersion
dc.rights.holder Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas es
dc.rights.holder Toledo, Flavia D. es
dc.rights.holder Basiglio, Cecilia Lorena es
dc.rights.holder Barosso, Ismael R. es
dc.rights.holder Boaglio, Andrea C. es
dc.rights.holder Zucchetti, Andrés E. es
dc.rights.holder Sanchez Pozzi, Enrique J. es
dc.rights.holder Roma, Marcelo G. es
dc.rights.holder Springer es
dc.relation.publisherversion http://dx.doi.org/10.1007/s00204-016-1898-1 es
dc.relation.publisherversion https://link.springer.com/article/10.1007%2Fs00204-016-1898-1 es
dc.rights.text Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0) es
dc.citation.title Archives of Toxicology es
dc.citation.volume 91(6) es
dc.description.fil Fil: Toledo, Flavia D. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Basiglio, Cecilia Lorena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Barosso, Ismael R. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Boaglio, Andrea C. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Zucchetti, Andrés E. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Sanchez Pozzi, Enrique J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.description.fil Fil: Roma, Marcelo G. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE-CONICET); Argentina. es
dc.type.collection articulo
dc.type.version publishedVersion es


Files in this item

The following license files are associated with this item:

This item appears in the following Collection(s)

Show simple item record

openAccess Except where otherwise noted, this item's license is described as openAccess

My Account


Search DSpace


Browse

Statistics