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

作者全名："Zhang, Lingbing; Zhang, Yandan; Qin, Xia; Jiang, Xuejun; Zhang, Jun; Mao, Lejiao; Jiang, Ziqi; Jiang, Yu; Liu, Gang; Qiu, Jingfu; Chen, Chengzhi; Qiu, Feng; Zou, Zhen"

作者地址："[Zhang, Lingbing; Qin, Xia; Qiu, Feng] Chongqing Med Univ, Dept Pharm, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Zhang, Yandan; Zhang, Jun; Mao, Lejiao; Jiang, Ziqi; Zou, Zhen] Chongqing Med Univ, Inst Life Sci, Mol Biol Lab Resp Dis, Chongqing 400016, Peoples R China; [Jiang, Xuejun] Chongqing Med Univ, Ctr Expt Teaching Publ Hlth, Expt Teaching & Management Ctr, Chongqing 400016, Peoples R China; [Zhang, Jun; Qiu, Jingfu; Chen, Chengzhi; Zou, Zhen] Chongqing Med Univ, Res Ctr Environm & Human Hlth, Sch Publ Hlth, Chongqing 400016, Peoples R China; [Jiang, Yu] Chongqing Med Univ, Dept Resp Med, Univ Town Hosp, Chongqing 401331, Peoples R China; [Liu, Gang] Chongqing Med Univ, Dept Emergency, Univ Town Hosp, Chongqing 401331, Peoples R China; [Qiu, Jingfu] Chongqing Med Univ, Sch Publ Hlth, Dept Hlth Lab Technol, Chongqing 400016, Peoples R China; [Chen, Chengzhi] Chongqing Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Chongqing 400016, Peoples R China"

通信作者："Qiu, F (通讯作者)，Chongqing Med Univ, Dept Pharm, Affiliated Hosp 1, Chongqing 400016, Peoples R China.; Zou, Z (通讯作者)，Chongqing Med Univ, Inst Life Sci, Mol Biol Lab Resp Dis, Chongqing 400016, Peoples R China.; Qiu, JF; Chen, CZ; Zou, Z (通讯作者)，Chongqing Med Univ, Res Ctr Environm & Human Hlth, Sch Publ Hlth, Chongqing 400016, Peoples R China.; Qiu, JF (通讯作者)，Chongqing Med Univ, Sch Publ Hlth, Dept Hlth Lab Technol, Chongqing 400016, Peoples R China.; Chen, CZ (通讯作者)，Chongqing Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Chongqing 400016, Peoples R China."

来源：CRITICAL CARE

ESI学科分类：　

WOS号：WOS:000809142500001

JCR分区：Q1

影响因子：15.1

年份：2022

卷号：26

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：SARS-CoV-2; Spike RBD; ACE2; Angiotensin II; Acute lung injury

摘要："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."

基金机构："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]"

基金资助正文："This research was supported by Science and Technology Research Program of Chongqing Education Commission (KYYJ202005 and KJCXZD2020020), Chongqing Talents: Exceptional Young Talents Project (CQYC2020058650 and CQYC2021058941), Natural Science Foundation of Chongqing (cstc2020jcyjmsxmX0155, cstc2020jcyj-zdxmX0029, cstc2021ycjh-bgzxm0105, cstc2021jcyj-msxmX0141 and cstc2020jcyj-msxmX0192), and Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0038)."