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ACE2 Expressed on Myeloid Cells Alleviates Sepsis-Induced Acute Liver Injury via the Ang-(1–7)–Mas Receptor Axis

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Abstract

Sepsis-induced acute liver injury (ALI) is common in intensive care units. Angiotensin-converting enzyme 2 (ACE2) plays a vital role in hepatic fibrosis and steatosis; however, its role in sepsis-induced ALI remains unclear. This study found that hepatic ACE2 expression in cecal ligation and puncture (CLP)-treated mice significantly decreased 24 h after CLP. ACE2-transgenic (TG) mice exhibited a significant improvement in CLP-induced ALI, accompanied by the inhibition of hepatocyte apoptosis, oxidative stress, and inflammation, while ACE2-knockout mice demonstrated an opposite trend. During sepsis-induced ALI, ACE2-TG could also elevate the Ang-(1–7) and Mas receptor (MasR) levels in liver tissues. Interestingly, the MasR inhibitor A779 abrogated the favorable effects of ACE2 on CLP-induced ALI. In a bone marrow transplantation experiment, the ACE2-TG transplantation group showed significantly improved inflammation and liver dysfunction, less hepatocyte apoptosis, and reduced oxidative stress after CLP compared with the wild-type transplantation group. In contrast, the ACE2-knockout group showed poor inflammatory response and liver dysfunction, significantly more hepatocyte apoptosis, and elevated oxidative stress than the wild-type transplantation group after CLP. ACE2 protects against sepsis-induced ALI by inhibiting hepatocyte apoptosis, oxidative stress, and inflammation via the Ang-(1–7)–Mas receptor axis. Thus, targeting ACE2 may be a promising novel strategy for preventing and treating sepsis-induced ALI.

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The data and materials used in this study are available from the corresponding authors upon reasonable request.

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This work was supported by the National Natural Science Foundation of China (82172123).

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  1. Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8, South Road of Worker’s Stadium, Chaoyang District, Beijing, 100020, China

    Lei Liu, Ya Li, Jia-Xin Li, Xue Xiao, Tian-Tian Wan, Hui-Hua Li & Shu-Bin Guo

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Contributions

Methodology: LL and YL; formal analysis: LL; validation: LL, YL, JL, and XX; software: LL; investigation: LL, YL, JL, XX, and TW; data curation: LL; visualization: LL; conceptualization: HL and SG; writing—original draft preparation: LL; writing-review and editing: HL and SG; supervision: SG; funding acquisition: SG. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Hui-Hua Li or Shu-Bin Guo.

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Liu, L., Li, Y., Li, JX. et al. ACE2 Expressed on Myeloid Cells Alleviates Sepsis-Induced Acute Liver Injury via the Ang-(1–7)–Mas Receptor Axis. Inflammation (2024). https://doi.org/10.1007/s10753-023-01949-5

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