Aldosterone inhibits EVs secretion through autophagic degradation of MVBs in LSECs leads to the activation of HSC

Abstract Background and aims: Increasing evidence have confirmed the important role of extracellular vesicles (EVs) in liver fibrosis. However, there are rarely study concerned about the EVs from liver sinusoidal endothelial cells (LSECs) in the activation of hepatic stellate cells(HSCs) and liver fibrosis. Our previous work has shown that Aldosterone (Aldo) may have potential to regulate EVs from LSECs via autophagy pathway, hence we try to investigate the role of Aldo in the regulation of LSECs’ EVs. Approach and results: Aldo were used to induce liver fibrosis in rats. Rat with LSEC-specific Atg5 knock down was used to investigate mechanisms of autophagy in LSECs drive by Aldo. EVs of LSECs was isolated and co-culture with HSCs to define it effects on the activation of HSCs. EVs of LSECs was also analyzed by RNA-sequencing. In this study we found that inhibiting autophagy in LSECs could reduce the extent of Aldo induced liver fibrosis. Aldo led to capillarization, excessive autophagy and multivesicular bodies (MVBs) degradation in LSECs which reduce its secretion of EVs. Interesting, the antifibrotic microRNA miR-342-5p was also downregulated in the EVs. Rats developed liver fibrosis and HSCs activation through specific knockdown the secretion of EVs in LSECs. Conclusion: In summary, the degradation of MVBs through Aldo induced autophagy promotes the quantity and quality change of LSEC-derived EVs, thereby leading to the activation of HSCs in liver fibrosis in hyperaldosteronism. By regulating the LSECs’ phenotype and its EVs secretion may be a promising strategy for treating liver fibrosis.