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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Date
2019-08-29
Authors
Klein, Sabine
Kleine, Carola-Ellen
Pieper, Andrea
Granzow, Michaela
Gautsch, Sebastian
Himmit, Mimoun
Kahrmann, Katharina
Schierwagen, Robert
Uschner, Frank Erhard
Magdaleno, Fernando
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Nature Publishing Group
Published Version
10.1038/s41598-019-48024-4
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Abstract
Prevalence 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.
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Keywords
Rats , Portal hypertension , Janus-kinase 2 , Mas receptor , Non-alcoholic fatty liver disease (NAFLD) , Fibrosis , Mechanisms of disease , Molecular medicine
Citation
Klein, 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/s41598-019-48024-4
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https://www.nature.com/articles/s41598-019-48024-4
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https://hdl.handle.net/10468/8707
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Pharmacology and Therapeutics - Journal Articles
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© 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/.