Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2023; 29(33): 4975-4990
Published online Sep 7, 2023. doi: 10.3748/wjg.v29.i33.4975
Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells
Ying Wu, Ai-Hong Yin, Jun-Tao Sun, Wei-Hua Xu, Chun-Qing Zhang
Ying Wu, Jun-Tao Sun, Wei-Hua Xu, Department of Gastroenterology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong Province, China
Ai-Hong Yin, Department of Gastroenterology, Shandong Second Provincial General Hospital, Jinan 250000, Shandong Province, China
Chun-Qing Zhang, Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
Author contributions: Wu Y, Xu WH, and Zhang CQ designed and coordinated the study; Wu Y, Sun JT, and Yin AH performed the experiments, acquired and analyzed data; Xu WH and Zhang CQ interpreted the data; Wu Y wrote the manuscript; All authors have read and approved the final manuscript.
Supported by Shandong Provincial Natural Science Foundation, No. ZR2021MH389.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals, NO. KYLL-2021 (KJ) A-0062, The Institutional Animal Care Committee of the Second Hospital, Cheeloo College of Medicine, Shandong University.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wei-Hua Xu, MD, PhD, Chief Doctor, Professor, Department of Gastroenterology, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan Street, Jinan 250033, Shandong Province, China. xuweihua1967@126.com
Received: May 25, 2023
Peer-review started: May 25, 2023
First decision: July 8, 2023
Revised: July 27, 2023
Accepted: August 15, 2023
Article in press: August 15, 2023
Published online: September 7, 2023
Processing time: 98 Days and 17.8 Hours
ARTICLE HIGHLIGHTS
Research background

Liver cirrhosis is a hallmark of end-stage chronic liver disease, which leads to millions of deaths each year. At present, the treatment options for liver fibrosis and cirrhosis are limited and often ineffective. Angiotensin-converting enzyme 2 (ACE2)-driven protective renin-angiotensin system (RAS) provides an effective therapeutic target for liver fibrosis. In addition, the study of liver fibrosis targeting hepatic stellate cell (HSC) autophagy has attracted more and more attention.

Research motivation

In addition to its effect on the RAS, whether ACE2 can affect liver fibrosis through other mechanisms remains unclear. Moreover, how to enhance the expression and activity of tissue-specific ACE2 to avoid its potential off-target effect is a problem to be solved. Using a suitable and efficient gene delivery system to achieve tissue-specific overexpression of ACE2 has pointed out a new direction for the targeted treatment of liver fibrosis.

Research objectives

The aim of this study is to determine the effect of ACE2 on HSC activation, proliferation, apoptosis and liver fibrosis by regulating autophagy. This study provides new ideas for exploring the molecular mechanism by which ACE2 inhibits liver fibrosis and hepatic sinusoidal remodeling.

Research methods

In this study, a mouse model of liver fibrosis was constructed, and adeno-associated viral vector technology, pathological staining, multifactor analysis, multicolor immunofluorescence staining, transmission electron microscopy, TUNEL apoptosis assays, western blot analysis and other experimental methods were used to comprehensively explore the relationship and mechanism among ACE2, autophagy and liver fibrosis.

Research results

In vivo experiments showed that rAAV2/8-ACE2 treatment could inhibit HSC activation and angiogenesis, induce HSC apoptosis, and alleviate HSC proliferation and liver fibrosis by inhibiting HSC autophagy. This study also demonstrated that ACE2 overexpression could inhibit HSC autophagy in mouse liver tissues through the Adenosine monophosphate activates protein kinases (AMPK)/mammalian target of rapamycin (mTOR) pathway. The completion of this study provides new ideas for the prevention and targeted treatment of liver fibrosis and portal hypertension.

Research conclusions

The study demonstrates that autophagy plays a crucial role in HSC activation and liver fibrosis. ACE2 overexpression can inhibit HSC activation and promote apoptosis by regulating HSC autophagy through the AMPK/mTOR pathway, thereby alleviating liver fibrosis and hepatic sinusoidal remodeling.

Research perspectives

The pathogenesis of liver fibrosis and cirrhosis is a complex process involving the interaction of various growth factors, cytokines, and vasoactive substances. We need further clinical research to improve patient treatment outcomes through advanced technologies such as drug carrier-targeted HSC-specific therapies.