Aldosterone stimulates the non-genomic signaling pathway of the mineralocorticoid receptor in hepatic stellate cells

Abstract

The number of chronic inflammatory liver diseases and secondary complications caused by their progression has risen in recent years. The renin-angiotensin-aldosterone system seems to play an important role in liver fibrosis as well as in portal hypertension. The mineralocorticoid hormone aldosterone is known to regulate blood pressure and sodium retention. Furthermore proliferative and pro-fibrotic effects of aldosterone have been described in other organ systems that have been shown to be mediated by a non-genomic signaling pathway of the mineralocorticoid receptor. Therefore we investigated whether aldosterone could have an impact in the development or progression of liver fibrosis and which cell type could mediate pro-fibrotic effects of aldosterone in the liver. To evaluate possible effects of the mineralocorticoid receptor mediating pro-fibrotic effects in the liver we stimulated different human cell lines with aldosterone. The hepatic stellate cell line hTERT-HSC as well as the hepatoma cell lines HepG2 and Hep3B were stimulated with aldosterone in concentrations between 0.1 and 100 nM. In addition HEK-293 cells were used as negative control. Already after a short time incubation of aldosterone we detected an increase in phosphorylation of ERK2 in hTERT-HSCs. ERK phosphorylation in hTERT-HSCs was dependent on concentration and incubation time of aldosterone. Neither in the hepatocellular carcinoma cell line HepG2 nor Hep3B aldosterone caused a fast activation of intracellular signaling cascades by activation of ERK1/2 that was also not observed in HEK-293 cells. Furthermore aldosterone stimulated c-Src phosphorylation exclusively in hTERT-HSCs. These fast effects of aldosterone are mediated by a non-genomic activity of the mineralocorticoid receptor that has also been shown to be c-Src-dependent in other models of fibrosis. As hepatic stellate cells are known to be the central cell type with fibrogenic activity in the liver, pathophysiological effects of aldosterone during liver fibrosis could possibly be mediated by the non-genomic actions of the mineralocorticoid receptor in hepatic stellate cells.