2. Academic Validation
  3. TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice

TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice

  • Int J Mol Sci. 2018 Mar 12;19(3):817. doi: 10.3390/ijms19030817.
Sara Crespo Yanguas 1,  Tereza C da Silva 2,  Isabel V A Pereira 3,  Joost Willebrords 4,  Michaël Maes 5,  Marina Sayuri Nogueira 6,  Inar Alves de Castro 7,  Isabelle Leclercq 8,  Guilherme R Romualdo 9,  Luís F Barbisan 10,  Luc Leybaert 11,  Bruno Cogliati 12,  Mathieu Vinken 13
Affiliations

Affiliations

  • 1 Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium. Sara.Crespo.Yanguas@vub.be.
  • 2 Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo 05508-270, Brazil. terezacs@usp.br.
  • 3 Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo 05508-270, Brazil. isabelveloso@gmail.com.
  • 4 Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium. Joost.Willebrords@vub.be.
  • 5 Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium. Michael.MC.Maes@vub.be.
  • 6 Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil. masayuri.nogueira@gmail.com.
  • 7 Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil. inar@usp.br.
  • 8 Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et clinique, Université Catholique de Louvain, 1200 Brussels, Belgium. isabelle.leclercq@uclouvain.be.
  • 9 Department of Pathology, Botucatu Medical School, UNESP-São Paulo State University, Botucatu 18600-000, Brazil. romualdo.gr15@gmail.com.
  • 10 Department of Pathology, Botucatu Medical School, UNESP-São Paulo State University, Botucatu 18600-000, Brazil. barbisan@ibb.unesp.br.
  • 11 Department of Basic Medical Sciences, Physiology Group, Ghent University, 9000 Ghent, Belgium. Luc.Leybaert@UGent.be.
  • 12 Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo 05508-270, Brazil. bcogliati@usp.br.
  • 13 Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium. Mathieu.Vinken@vub.be.
PMID: 29534516 DOI: 10.3390/ijms19030817
Abstract

Although 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.

Keywords

connexin43; gap junction; hemichannel; hepatic stellate cells; inflammation; liver fibrosis.

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