ACE2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells

Background: Liver fibrosis is the common pathological process associated with the occurrence and development of various chronic liver diseases. Angiotensin converting enzyme 2 (ACE2) is a key negative regulator of renin-angiotensin system, and its specific molecular mechanism on hepatic stellate cell (HSC) autophagy and liver fibrosis needs to be further explored. Aim: To evaluate the effect of ACE2 on hepatic fibrosis in mice by regulating HSC autophagy through the AMPK/mTOR pathway. Methods: Overexpression of ACE2 in a mouse liver fibrosis model was induced by injection of rAAV2/8-ACE2 vector. The degree of liver fibrosis was assessed and the levels of biomarkers in serum were measured. The changes in the number of apoptotic HSCs and autophagosomes were examined. The effects of ACE2 overexpression on autophagy-related proteins and AMPK pathway-related proteins were analyzed. Results: rAAV2/8-ACE2 administration alleviated the degree of liver fibrosis and decreased the levels of VEGF and angiotensin II. In addition, the expression of α-SMA, fibronectin, and CD31 was down-regulated in the rAAV2/8-ACE2 group. There were more apoptotic HSCs in the rAAV2/8-ACE2 group than in the carbon tetrachloride and rapamycin groups. Moreover, rAAV2/8-ACE2 injection notably decreased the number of autophagosomes and the expression of autophagy-related proteins, and affected the expression of AMPK pathway-related proteins. Conclusions: ACE2 overexpression can inhibit HSC activation and promote cell apoptosis by regulating HSC autophagy through the AMPK/mTOR pathway, thereby alleviating liver fibrosis and hepatic sinusoidal remodeling.