Journal
CRITICAL CARE
Volume 26, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13054-022-04034-9
Keywords
SARS-CoV-2; Spike RBD; ACE2; Angiotensin II; Acute lung injury
Categories
Funding
- Science and Technology Research Program of Chongqing Education Commission [KYYJ202005, KJCXZD2020020]
- Chongqing Talents: Exceptional Young Talents Project [CQYC2020058650, CQYC2021058941]
- Natural Science Foundation of Chongqing [cstc2020jcyjmsxmX0155, cstc2020jcyj-zdxmX0029, cstc2021ycjh-bgzxm0105, cstc2021jcyj-msxmX0141, cstc2020jcyj-msxmX0192]
- Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0038]
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This study demonstrates that rACE2 plays a protective role against SARS-CoV-2 spike RBD protein-aggravated LPS-induced ALI in an animal model and illustrates the potential mechanism involving the ACE2-AngII-AT(1)R-NOX1/2 axis in SARS-CoV-2-induced ALI.
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 AT(1)R, 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-AT(1)R-NOX1/2 axis might contribute to SARS-CoV-2-induced ALI.
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