Importance of the non-physiological activation of the mineralocorticoid receptor for progression and development of complication in cirrhosis

点击翻译按钮获取中文摘要

Our previous results showed less progression of cirrhosis due to administration of the mineralocorticoid receptor (MR) antagonist Eplerenon during development of cirrhosis defined by less development of ascites, lower portal pressure, less shunts and less fibrotic tissue. An unphysiological activation of the MR under hypoxia and inhibition by Eplereonon was revealed as underlying mechanism.The aim of the proposal is the mechanistic characterisation of the MR in development and progression of cirrhosis. We want to clarify the role of the MR and the knowledge about the pathophysiology of the progress from fibrosis to cirrhosis and of decompensation for novel therapeutic strategies and prevention of disease progression. The following sub-projects are planned:A: Molecular systematics and mechanism of the altered MR expression and activation in hepatocytes.In primary hepatocytes the transcription, translocation and degradation of the MR in absence or presence of relevant stress conditions are planned to explain the lower concentration of the MR in cirrhosis. Cell lines (siRNA-transfection) are used to investigate molecular pathways in detail. B: Cellular changes and influence of cell-cell interaction by the unphysiological activation of the MR and its inhibition.The importance of the MR by measurement of specific MR-related genes for development of cirrhosis in presence or absence of Eplerenon will be investigated in different stages of fibrosis and cirrhosis. Upstream and downstream relevance of these findings will be further investigated. Cell-cell interaction from hepatocytes, stellate cells and sinusoidal endothelial cells in different stages of fibrosis and cirrhosis are planned to clarify the functional properties of the different cells and the importance of cell-cell communication using coculture with or without cell-cell contact. C: Importance of the unphysiological activation in cirrhosis for liver perfusion, vascular dysfunction and vascular endothelial phenotype.The importance of the MR for portal-venous and hepatic arterial dysfunction in cirrhosis will be investigated by using liver perfusion models. Functional properties of the portal vein and the hepatic artery will be determined by Mulvany-Myography and isometric contraction. Endothelial cells from portal veins and hepatic arteries will be cultured and receptors, growth factors and secondary mediators investigated.