Aldosterone induces hepatic stellate cells activation and liver fibrosis through Cav-1 dependent pathway

Abstract Hepatic stellate cell (HSC) activation is a pivotal event in liver fibrosis. Aldosterone (Aldo) is upregulated in liver fibrosis, but its role in HSC activation remains unclear. Caveolin-1 (Cav-1) is a key structural protein of caveolae that facilitates the actions of Aldo in various cellular processes. However, the expression and function of Cav-1 in HSCs during HSC activation and liver fibrosis are controversial. Our findings demonstrate that the intracellular expression of Aldo and Cav-1 is upregulated during HSC activation. Administration of spironolactone or knockdown of Cav-1 in HSCs resulted in ameliorated liver fibrosis induced by Aldo infusion or bile duct ligation (BDL) in rats. Mechanistically, Aldo recruited proteins such as mineralocorticoid receptor (MR), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), and NADPH oxidase 4 (NOX4) into HSC caveolae via Cav-1, thereby elevating intracellular levels of interleukin-1β (IL-1β) and reactive oxygen species (ROS), consequently enhancing HSC contraction and migration abilities. Our study reveals a novel mechanism through which Aldo regulates HSC activation and promotes liver fibrosis via the Cav-1 dependent pathway, highlighting the therapeutic potential of blocking the Aldo receptor or specifically targeting intracellular Cav-1 to ameliorate cholestatic liver fibrosis.