TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice

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dc.contributor.authorYanguas, Sara Crespo
dc.contributor.authorda Silva, Tereza C.
dc.contributor.authorPereira, Isabel V. A.
dc.contributor.authorWillebrords, Joost
dc.contributor.authorMaes, Michaël
dc.contributor.authorNogueira, Marina Sayuri
dc.contributor.authorde Castro, Inar Alves
dc.contributor.authorLeclercq, Isabelle
dc.contributor.authorRomualdo, Guilherme R. [UNESP]
dc.contributor.authorBarbisan, Luís F. [UNESP]
dc.contributor.authorLeybaert, Luc
dc.contributor.authorCogliati, Bruno
dc.contributor.authorVinken, Mathieu
dc.contributor.institutionVrije Universiteit Brussel
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversité Catholique de Louvain
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionGhent University
dc.date.accessioned2018-12-11T17:18:37Z
dc.date.available2018-12-11T17:18:37Z
dc.date.issued2018-03-12
dc.description.abstractAlthough a plethora of signaling pathways are known to drive the activation of hepatic stellate cells in liver fibrosis, the involvement of connexin-based communication in this process remains elusive. Connexin43 expression is enhanced in activated hepatic stellate cells and constitutes the molecular building stone of hemichannels and gap junctions. While gap junctions support intercellular communication, and hence the maintenance of liver homeostasis, hemichannels provide a circuit for extracellular communication and are typically opened by pathological stimuli, such as oxidative stress and inflammation. The present study was set up to investigate the effects of inhibition of connexin43-based hemichannels and gap junctions on liver fibrosis in mice. Liver fibrosis was induced by administration of thioacetamide to Balb/c mice for eight weeks. Thereafter, mice were treated for two weeks with TAT-Gap19, a specific connexin43 hemichannel inhibitor, or carbenoxolone, a general hemichannel and gap junction inhibitor. Subsequently, histopathological analysis was performed and markers of hepatic damage and functionality, oxidative stress, hepatic stellate cell activation and inflammation were evaluated. Connexin43 hemichannel specificity of TAT-Gap19 was confirmed in vitro by fluorescence recovery after photobleaching analysis and the measurement of extracellular release of adenosine-5′-triphosphate. Upon administration to animals, both TAT-Gap19 and carbenoxolone lowered the degree of liver fibrosis accompanied by superoxide dismutase overactivation and reduced production of inflammatory proteins, respectively. These results support a role of connexin-based signaling in the resolution of liver fibrosis, and simultaneously demonstrate the therapeutic potential of TAT-Gap19 and carbenoxolone in the treatment of this type of chronic liver disease.en
dc.description.affiliationDepartment of In Vitro Toxicology and Dermato-Cosmetology Vrije Universiteit Brussel
dc.description.affiliationDepartment of Pathology School of Veterinary Medicine and Animal Science University of São Paulo
dc.description.affiliationDepartment of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São Paulo
dc.description.affiliationLaboratory of Hepatogastroenterology Institut de Recherche Expérimentale et clinique Université Catholique de Louvain
dc.description.affiliationDepartment of Pathology Botucatu Medical School UNESP-São Paulo State University
dc.description.affiliationDepartment of Basic Medical Sciences Physiology Group Ghent University
dc.description.affiliationUnespDepartment of Pathology Botucatu Medical School UNESP-São Paulo State University
dc.description.sponsorshipEuropean Research Council
dc.description.sponsorshipIdEuropean Research Council: 335476
dc.identifierhttp://dx.doi.org/10.3390/ijms19030817
dc.identifier.citationInternational Journal of Molecular Sciences, v. 19, n. 3, 2018.
dc.identifier.doi10.3390/ijms19030817
dc.identifier.file2-s2.0-85044157317.pdf
dc.identifier.issn1422-0067
dc.identifier.issn1661-6596
dc.identifier.scopus2-s2.0-85044157317
dc.identifier.urihttp://hdl.handle.net/11449/176027
dc.language.isoeng
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.relation.ispartofsjr1,260
dc.rights.accessRightsAcesso aberto
dc.sourceScopus
dc.subjectConnexin43
dc.subjectGap junction
dc.subjectHemichannel
dc.subjectHepatic stellate cells
dc.subjectInflammation
dc.subjectLiver fibrosis
dc.titleTAT-Gap19 and Carbenoxolone alleviate liver fibrosis in miceen
dc.typeArtigo
unesp.author.orcid0000-0003-3195-6817[1]
unesp.author.orcid0000-0001-8092-928X[6]
unesp.author.orcid0000-0001-8092-928X[10]
unesp.author.orcid0000-0001-6452-6982[11]

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