Mechanisms Of Aldosterone Inducing Hepatic Stellate Cells Activation And Liver Fibrosis Via Caveolin-1

BackgroundThousands of people suffer from chronic hepatic fibrosis in the worldwide,and about 25%-30%of patients with hepatic fibrosis can further develop into cirrhosis.An in-depth study of the hepatic fibrosis pathogenesis is important for the development of new diagnostic methods and treatment options.Activation of hepatic stellate cells(HSCs)is a core event in the process of hepatic fibrosis.The activated HSCs can surround and contract the hepatic microvessels,then produce a large amount of extracellular matrix,which can promote the progression of hepatic fibrosis.Previous studies have demonstrated that aldosterone has a role in promoting contraction and migration of hepatic stellate cells.Since aldosterone can induce a variety of intracellular inflammation and oxidative stress imbalance,which are closely related to the activation of hepatic stellate cells,the relationship between aldosterone,inflammation and oxidative stress in hepatic stellate cells is of great significance.The caveolae is a structure on the cytoplasmic membrane that can transmit multiple stimuli signals and induce intracellular inflammation and oxidative stress.Since aldosterone's multiple physiological functions can be completed by the caveolae,it is worthy of further study whether aldosterone can promote the activation of HSCs through the caveolae structure.ObjectiveTo explore the roles and mechanisms of aldosterone and caveolae in HSCs activation and hepatic fibrosis.Methods1.In vitro experiment:the effects of aldosterone on prnmary rat HSCs phenotype and function were studied to explore the mechanisms of aldosterone in HSCs activation;2.In vivo experiments:the hepatic fibrosis models induced by cholestasis or hyperaldosteronemia in rats were used to investigate the mechanisms of aldosterone and caveolae in hepatic fibrosis.3.Clinical validation:liver tissues from patients with hepatic fibrosis were collected and used to verify the mechanisms of aldosterone and caveolae in hepatic fibrosis.Result1.Aldosterone promoted the production of IL-1? and reactive oxygen species through caveolin-1-dependent genomic and non-genomic pathways,activated the related pathways about contraction,migration and collagen synthesis,and induced primary rat HSCs activation;2.In the rat liver fibrosis models that established by hyperaldosteronism or cholestasis,the inflammation and oxidative stress were induced by aldosterone and caveolin-1 in HSCs,and the associated proteins of contraction,migration,and collagen synthesis.pathways were up-regulated,which was important for the activation of HSCs and the development of liver fibrosis;3.Aldosterone and caveolin-1 could promote the activation of hepatic stellate cells from patients with liver fibrosis through the similar pathways as primary rat HSCs.ConclusionAldosterone induces HSCs activation via caveolin-1-dependent genomic and non-genomic pathways that promotes the expressions of related proteins about inflammation and oxidative stress in HSCs,which increases the production of IL-1? and reactive oxygen species and enhances HSCs abilities of contraction,migration and collagen generation.Aldosterone and caveolin-1 play important roles in the development and progression of hepatic fibrosis.