Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress
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 canalicula...
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| Autores principales: | , , , , , , |
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| Formato: | article artículo publishedVersion |
| Lenguaje: | Inglés |
| Publicado: |
Springer
2019
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| Materias: | |
| Acceso en línea: | http://hdl.handle.net/2133/13924 http://hdl.handle.net/2133/13924 |
| Aporte de: |
| id |
I15-R121-2133-13924 |
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| record_format |
dspace |
| institution |
Universidad Nacional de Rosario |
| institution_str |
I-15 |
| repository_str |
R-121 |
| collection |
Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR) |
| language |
Inglés |
| orig_language_str_mv |
eng |
| topic |
Oxidative stress Hepatocellular cholestasis Canalicular transporters Mitogen-activated protein kinases Actin cytoskeleton |
| spellingShingle |
Oxidative stress Hepatocellular cholestasis Canalicular transporters Mitogen-activated protein kinases Actin cytoskeleton Toledo, Flavia D. Basiglio, Cecilia Lorena Barosso, Ismael R. Boaglio, Andrea C. Zucchetti, Andrés E. Sanchez Pozzi, Enrique J. Roma, Marcelo Gabriel Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress |
| topic_facet |
Oxidative stress Hepatocellular cholestasis Canalicular transporters Mitogen-activated protein kinases Actin cytoskeleton |
| 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. |
| format |
article artículo publishedVersion |
| author |
Toledo, Flavia D. Basiglio, Cecilia Lorena Barosso, Ismael R. Boaglio, Andrea C. Zucchetti, Andrés E. Sanchez Pozzi, Enrique J. Roma, Marcelo Gabriel |
| author_facet |
Toledo, Flavia D. Basiglio, Cecilia Lorena Barosso, Ismael R. Boaglio, Andrea C. Zucchetti, Andrés E. Sanchez Pozzi, Enrique J. Roma, Marcelo Gabriel |
| author_sort |
Toledo, Flavia D. |
| title |
Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress |
| title_short |
Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress |
| title_full |
Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress |
| title_fullStr |
Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress |
| title_full_unstemmed |
Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress |
| title_sort |
mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress |
| publisher |
Springer |
| publishDate |
2019 |
| url |
http://hdl.handle.net/2133/13924 http://hdl.handle.net/2133/13924 |
| work_keys_str_mv |
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Repositorios |
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