{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:21:50Z","timestamp":1790256110412,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2018,6,7]],"date-time":"2018-06-07T00:00:00Z","timestamp":1528329600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Wilhelm Roux Program of Medical Faculty of the Martin Luther University"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The mineralocorticoid receptor (MR) contributes to fibrosis in various tissues, and MR antagonists, like eplerenone, are used to prevent fibrosis. The role of MR antagonists in hepatic fibrosis and cirrhosis is unknown. Here, we investigated the role of MRs and eplerenone in cirrhosis development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Liver fibrosis (5\u00a0weeks) and cirrhosis, without (8\u00a0weeks) and with ascites (12\u00a0weeks), were induced by CCl<jats:sub>4<\/jats:sub> in rats and comprehensively analysed. The effect of eplerenone on the development of cirrhosis with ascites was assessed. MR expression, cellular and subcellular distribution and impact of hypoxia were investigated <jats:italic>in vivo<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic>. Primary rat hepatocytes and cell lines were used to investigate MR trafficking and transcriptional activity mechanistically.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In cirrhosis with ascites, MR mRNA and protein expressions were reduced in hepatocytes of hypoxic areas. While in normoxic areas MRs were mainly cytosolic, the remaining MRs in hypoxic areas were mainly localized in the nuclei, indicating activation followed by translocation and degradation. Accordingly, eplerenone treatment prevented nuclear MR translocation and the worsening of cirrhosis. Exposing hepatocytes <jats:italic>ex vivo<\/jats:italic> to hypoxia induced nuclear MR translocation and enhanced transcriptional MR activity at response elements of the NF\u2010\u03baB pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>We showed for the first time that hypoxia leads to a pathogenetic ligand\u2010independent activation of hepatic MRs during cirrhosis resulting in their nuclear translocation and transcriptional activation of the NF\u2010\u03baB pathway. Treatment with eplerenone prevented the worsening of cirrhosis by blocking this ligand\u2010independent activation of the MR.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14341","type":"journal-article","created":{"date-parts":[[2018,4,23]],"date-time":"2018-04-23T01:15:44Z","timestamp":1524446144000},"page":"2956-2967","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis"],"prefix":"10.1111","volume":"175","author":[{"given":"Barbara","family":"Schreier","sequence":"first","affiliation":[{"name":"Julius Bernstein Institute of Physiology, Medical School Martin Luther University of Halle\u2010Wittenberg  Halle Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Wolf","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Hepatology, Clinic of Internal 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