Hypoxia and inflammation reduce the expression of the mineralocorticoid receptor (MR) in the hepatocytes – a mechanism that explains the lower expression of MR in cirrhosis

Introduction: Hypoxia and inflammation are the main mechanisms in the development of cirrhosis. Cirrhosis leads to increased concentration of aldosterone. Aldosterone activates the MR. The aim was to investigate the role of MR during the development of cirrhosis.

Methods: Fibrosis and cirrhosis was induced by CCl4 administration for 5, 8 or 12 weeks (w). Total liver tissue, hepatocytes (Hep), hepatic stellate cells (HSC) and endothelial cells (LSEC) were isolated. Gene expression was analyzed using qRT-PCR and droplet digital PCR. Hepatoma cells (MH1C1) were treated with cytokines (IL-1ß, IL-6 and TNF-α each 10 ng/ml) and hypoxia (0.1% O2) for 24 hours.

Results: In normal livers copy number of MR mRNA was increased 10-fold in Hep (mean ± SEM: 9914 ± 2622 mRNA/µg RNA) compared to HSC (1027 ± 275; p < 0.05) and LSEC (1280 ± 120; p < 0.05). Developing of cirrhosis led to reduction of MR in Hep (8w: 52 ± 4.9%, p < 0.05; 12w: 6.0 ± 3.0%, p < 0.01) compared to normal (100%). Treatment of MH1C1 with cytokines alone did not change the expression of MR. Hypoxia alone leads to a decrease in MR mRNA (compared to normoxia: 22 ± 3.5%; p < 0.01) and protein (51 ± 5.6%; p < 0.05). Co-incubation using cytokines and hypoxia revealed a decrease of MR mRNA (13 ± 1.1%; p < 0.01) and protein (18 ± 2.9%; p < 0.01).

Conclusion: MR is mainly expressed in Hepatocytes and less in HSC or LSEC. Expression of MR decreases during the development of cirrhosis in Hepatocytes. Hypoxia reduces the expression of MR in Hepatocytes. Combination of hypoxia and inflammation further decrease the expression of MR. These results might explain the decrease in MR expression in liver cirrhosis.

Corresponding author: Wolf, Anja

E-Mail: [e-mail]