Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA217

Poster Communications

The selective mineralcorticoid receptor (MR) antagonist eplerenon prevents decompensation of liver cirrhosis.

B. Schreier1, A. Wolf1,2, S. Hammer2, S. Pohl2, S. Mildenberger1, S. Rabe1, M. Gekle1, A. Zipprich2

1. Julius-Bernstein Institute of Physiology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany. 2. Clinics for internal medicine I, Martin Luther University of Halle-Wittenberg, Halle/Saale, Germany.

Background & aims: The MR contributes to fibrosis in various tissues and MR antagonists, like eplerenone, are used to prevent fibrosis. The role of MR antagonists for hepatic fibrosis and cirrhosis is unknown. Here, we investigated the role of MR and eplerenone in cirrhosis development. Methods: Liver fibrosis (5 weeks), cirrhosis without (8w) and with ascites (12w) were induced by CCl4 in rats and comprehensively analyzed. In addition the effect of eplerenone (MR antagonist) on the development of cirrhosis with ascites was assessed. With respect to MR expression, cellular and subcellular distribution as well as impact of hypoxia were investigated in vivo and ex vivo. Primary rat hepatocytes and cell lines were used to investigate MR trafficking and transcriptional activity mechanistically. Results: In the liver the main celltype expressing the MR are hepatocytes. Blood plasma aldosterone levels increased significantly already during the first 5w and remained stable thereafter for 8w and 12w of CCl4 treatment. In cirrhosis with ascites MR-mRNA and -protein expression were reduced in hepatocytes of hypoxic areas. While in normoxic areas MR was mainly cytosolic, the remaining MR in hypoxic areas was mainly localized in the nuclei, indicating activation followed by translocation and degradation. We also analyzed the expression of the glucocorticoid receptor, the nearest relative to the MR. GR revealed no change in expression during cirrhosis with ascites. The decrease of MR was detectable only in liver tissue. We did not observe any differences in MR mRNA or protein in renal or heart tissue from cirrhotic compared to control animals. Exposing hepatocytes ex vivo to hypoxia also induced nuclear MR translocation and enhanced transcriptional MR-activity at response elements of the NFkB pathway. Visual evaluation of the liver surface showed significant less nodules, less shunts and less ascites in the eplerenone treated group compared to cirrhotic animals without eplerenone. Quantification of fibrosis using Sirius red staining revealed significantly less fibrosis in animals treated with eplerenone. Furthermore, in treated animals the liver weight was significantly higher, the spleen weight and the heart weight significantly lower compared to non-treated group. Accordingly, eplerenone treatment prevented nuclear MR translocation and worsening of cirrhosis. Conclusion: We show for the first time that hypoxia leads to a pathogenetic relevant ligand independent activation of hepatic MR during cirrhosis with subsequent nuclear translocation and transcriptional activation of the NFkB pathway. Treatment with the MR antagonist eplerenone prevented worsening of cirrhosis by blocking the ligand independent activation of the MR.

Where applicable, experiments conform with Society ethical requirements