2. Academic Validation
  3. Recombinant ACE2 protein protects against acute lung injury induced by SARS-CoV-2 spike RBD protein

Recombinant ACE2 protein protects against acute lung injury induced by SARS-CoV-2 spike RBD protein

  • Crit Care. 2022 Jun 9;26(1):171. doi: 10.1186/s13054-022-04034-9.
Lingbing Zhang  # 1,  Yandan Zhang  # 2,  Xia Qin  # 1,  Xuejun Jiang 3,  Jun Zhang 2 4,  Lejiao Mao 2,  Ziqi Jiang 2,  Yu Jiang 5,  Gang Liu 6,  Jingfu Qiu 7 8,  Chengzhi Chen 9 10,  Feng Qiu 11,  Zhen Zou 12 13
Affiliations

Affiliations

  • 1 Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 2 Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 3 Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 4 Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 5 Department of Respiratory Medicine, The University-Town Hospital of Chongqing Medical University, Chongqing, 401331, People's Republic of China.
  • 6 Department of Emergency, The University-Town Hospital of Chongqing Medical University, Chongqing, 401331, People's Republic of China.
  • 7 Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China. jfqiu@126.com.
  • 8 Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China. jfqiu@126.com.
  • 9 Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China. chengzhichen@cqmu.edu.cn.
  • 10 Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China. chengzhichen@cqmu.edu.cn.
  • 11 Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China. 923189400@qq.com.
  • 12 Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China. zouzhen@cqmu.edu.cn.
  • 13 Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China. zouzhen@cqmu.edu.cn.
  • # Contributed equally.
PMID: 35681221 DOI: 10.1186/s13054-022-04034-9
Abstract

Background: SARS-CoV-2 Infection leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Both clinical data and animal experiments suggest that the renin-angiotensin system (Ras) is involved in the pathogenesis of SARS-CoV-2-induced ALI. Angiotensin-converting Enzyme 2 (ACE2) is the functional receptor for SARS-CoV-2 and a crucial negative regulator of Ras. Recombinant ACE2 protein (rACE2) has been demonstrated to play protective role against SARS-CoV and avian influenza-induced ALI, and more relevant, rACE2 inhibits SARS-CoV-2 proliferation in vitro. However, whether rACE2 protects against SARS-CoV-2-induced ALI in animal models and the underlying mechanisms have yet to be elucidated.

Methods and results: Here, we demonstrated that the SARS-CoV-2 spike receptor-binding domain (RBD) protein aggravated lipopolysaccharide (LPS)-induced ALI in mice. SARS-CoV-2 spike RBD protein directly binds and downregulated ACE2, leading to an elevation in angiotensin (Ang) II. AngII further increased the NOX1/2 through AT1R, subsequently causing oxidative stress and uncontrolled inflammation and eventually resulting in ALI/ARDS. Importantly, rACE2 remarkably reversed SARS-CoV-2 spike RBD protein-induced ALI by directly binding SARS-CoV-2 spike RBD protein, cleaving AngI or cleaving AngII.

Conclusion: This study is the first to prove that rACE2 plays a protective role against SARS-CoV-2 spike RBD protein-aggravated LPS-induced ALI in an animal model and illustrate the mechanism by which the ACE2-AngII-AT1R-NOX1/2 axis might contribute to SARS-CoV-2-induced ALI.

Keywords

ACE2; Acute lung injury; Angiotensin II; SARS-CoV-2; Spike RBD.

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