TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor

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dc.contributor.authorKlein, Sabine
dc.contributor.authorKleine, Carola-Ellen
dc.contributor.authorPieper, Andrea
dc.contributor.authorGranzow, Michaela
dc.contributor.authorGautsch, Sebastian
dc.contributor.authorHimmit, Mimoun
dc.contributor.authorKahrmann, Katharina
dc.contributor.authorSchierwagen, Robert
dc.contributor.authorUschner, Frank Erhard
dc.contributor.authorMagdaleno, Fernando
dc.contributor.authorNaoum, Maria Eleni
dc.contributor.authorKristiansen, Glen
dc.contributor.authorWalther, Thomas
dc.contributor.authorBader, Michael
dc.contributor.authorSauerbruch, Tilman
dc.contributor.authorTrebicka, Jonel
dc.contributor.funderDeutsche Forschungsgemeinschaften
dc.contributor.funderFundación Cellexen
dc.contributor.funderHorizon 2020en
dc.contributor.funderH2020 Societyen
dc.date.accessioned2019-10-06T21:10:08Z
dc.date.available2019-10-06T21:10:08Z
dc.date.issued2019-08-29
dc.description.abstractPrevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.en
dc.description.sponsorshipDeutsche Forschungsgemeinschaft (SFB TRR57 P18)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid11598en
dc.identifier.citationKlein, S., Kleine, C.-E., Pieper, A., Granzow, M., Gautsch, S., Himmit, M., Kahrmann, K., Schierwagen, R., Uschner, F. E., Magdaleno, F., Naoum, M. E., Kristiansen, G., Walther, T., Bader, M., Sauerbruch, T. and Trebicka, J. (2019) 'TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor', Scientific Reports, 9(1), 11598. (10pp.) DOI: 10.1038/s41598-019-48024-4en
dc.identifier.doi10.1038/s41598-019-48024-4en
dc.identifier.eissn2045-2322
dc.identifier.endpage10en
dc.identifier.issued1en
dc.identifier.journaltitleScientific Reportsen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/8707
dc.identifier.volume9en
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/H2020::SME-1/808677/EU/PREDICT/PREDICTen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/H2020::RIA/668031/EU/GALAXY: Gut-and-liver axis in alcoholic liver fibrosis/GALAXYen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/H2020::RIA/731875/EU/SIMVASTATIN AND RIFAXIMIN AS NEW THERAPY FOR PATIENTS WITH DECOMPENSATED CIRRHOSIS/LIVERHOPEen
dc.relation.urihttps://www.nature.com/articles/s41598-019-48024-4
dc.rights© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectRatsen
dc.subjectPortal hypertensionen
dc.subjectJanus-kinase 2en
dc.subjectMas receptoren
dc.subjectNon-alcoholic fatty liver disease (NAFLD)en
dc.subjectFibrosisen
dc.subjectMechanisms of diseaseen
dc.subjectMolecular medicineen
dc.titleTGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptoren
dc.typeArticle (peer-reviewed)en
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