{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:31:25Z","timestamp":1787790685984,"version":"build-2784847793"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["24-136"],"award-info":[{"award-number":["24-136"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20H03426, 20K21566"],"award-info":[{"award-number":["20H03426, 20K21566"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.<\/jats:p>","DOI":"10.3389\/fimmu.2021.732690","type":"journal-article","created":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T05:17:03Z","timestamp":1640150223000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":63,"title":["Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19"],"prefix":"10.3389","volume":"12","author":[{"given":"Keiji","family":"Kuba","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomokazu","family":"Yamaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef M.","family":"Penninger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1139\/y02-021","article-title":"ACEH\/ACE2 Is a Novel Mammalian Metallocarboxypeptidase and a Homologue of Angiotensin-Converting Enzyme Insensitive to ACE Inhibitors","volume":"80","author":"Turner","year":"2002","journal-title":"Can J Physiol Pharmacol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/S1050-1738(02)00233-5","article-title":"The Role of ACE2 in Cardiovascular Physiology","volume":"13","author":"Oudit","year":"2003","journal-title":"Trends Cardiovasc Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2010.06.003","article-title":"Trilogy of ACE2: A Peptidase in the Renin-Angiotensin System, a SARS Receptor, and a Partner for Amino Acid Transporters","volume":"128","author":"Kuba","year":"2010","journal-title":"Pharmacol Ther"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-12-1544","article-title":"Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases","volume":"77","author":"Kuba","year":"2013","journal-title":"Circ J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2012-7","article-title":"A Pneumonia Outbreak Associated With a New Coronavirus of Probable Bat Origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic Characterization and Epidemiology of 2019 Novel Coronavirus: Implications for Virus Origins and Receptor Binding","volume":"395","author":"Lu","year":"2020","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1016\/j.cub.2020.03.022","article-title":"Probable Pangolin Origin of SARS-CoV-2 Associated With the COVID-19 Outbreak","volume":"30","author":"Zhang","year":"2020","journal-title":"Curr Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1038\/s41564-021-00908-w","article-title":"The Furin Cleavage Site in the SARS-CoV-2 Spike Protein Is Required for Transmission in Ferrets","author":"Peacock","year":"2021","journal-title":"Nat Microbiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.103275","article-title":"Elastase-Mediated Activation of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein at Discrete Sites Within the S2 Domain","volume":"285","author":"Belouzard","year":"2010","journal-title":"J Biol Chem"},{"key":"B12","doi-asserted-by":"publisher","first-page":"104760","DOI":"10.1016\/j.meegid.2021.104760","article-title":"SARS-Cov-2 Mutation 614G Creates an Elastase Cleavage Site Enhancing Its Spread in High AAT-Deficient Regions","volume":"90","author":"Bhattacharyya","year":"2021","journal-title":"Infect Genet Evol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.45498","article-title":"Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19","volume":"16","author":"Yang","year":"2020","journal-title":"Int J Biol Sci"},{"key":"B14","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/s41392-020-00426-x","article-title":"CD147-Spike Protein Is a Novel Route for SARS-Cov-2 Infection to Host Cells","volume":"5","author":"Wang","year":"2020","journal-title":"Signal Transduct Target Ther"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1101\/2020.05.13.092478","article-title":"Novel ACE2-Independent Carbohydrate-Binding of SARS-CoV-2 Spike Protein to Host Lectins and Lung Microbiota","author":"Chiodo","year":"2020","journal-title":"Biorxiv"},{"key":"B16","doi-asserted-by":"crossref","first-page":"e1009576","DOI":"10.1371\/journal.ppat.1009576","article-title":"DC\/L-SIGN Recognition of Spike Glycoprotein Promotes SARS-Cov-2 Trans-Infection and can be Inhibited by a Glycomimetic Antagonist","volume":"17","author":"Th\u00e9paut","year":"2021","journal-title":"PloS Pathog"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd3072","article-title":"Neuropilin-1 Is a Host Factor for SARS-CoV-2 Infection","volume":"370","author":"Daly","year":"2020","journal-title":"Science"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.04.004","article-title":"Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2","volume":"181","author":"Monteil","year":"2020","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30418-5","article-title":"Human Recombinant Soluble ACE2 in Severe COVID-19","volume":"8","author":"Zoufaly","year":"2020","journal-title":"Lancet Respir Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nm1267","article-title":"A Crucial Role of Angiotensin Converting Enzyme 2 (ACE2) in SARS Coronavirus-Induced Lung Injury","volume":"11","author":"Kuba","year":"2005","journal-title":"Nat Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"17021","DOI":"10.1038\/celldisc.2017.21","article-title":"MiRNA-200c-3p Is Crucial in Acute Respiratory Distress Syndrome","volume":"3","author":"Liu","year":"2017","journal-title":"Cell Discovery"},{"key":"B22","doi-asserted-by":"publisher","first-page":"6791","DOI":"10.1038\/s41467-021-27097-8","article-title":"ACE2-Like Carboxypeptidase B38-CAP Protects From SARS-Cov-2-Induced Lung Injury. Researchsquare.Com\/Article\/Rs-124634\/V2","volume":"12","author":"Yamaguchi","year":"2021","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M200581200","article-title":"Hydrolysis of Biological Peptides by Human Angiotensin-Converting Enzyme-Related Carboxypeptidase","volume":"277","author":"Vickers","year":"2002","journal-title":"J Biol Chem"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nature00786","article-title":"Angiotensin-Converting Enzyme 2 Is an Essential Regulator of Heart Function","volume":"417","author":"Crackower","year":"2002","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.2108086","article-title":"Angiotensin Converting Enzyme Insertion\/Deletion Polymorphism Is Associated With Susceptibility and Outcome in Acute Respiratory Distress Syndrome","volume":"166","author":"Marshall","year":"2002","journal-title":"Am J Respir Crit Care Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nature03712","article-title":"Angiotensin-Converting Enzyme 2 Protects From Severe Acute Lung Failure","volume":"436","author":"Imai","year":"2005","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1038\/s41467-020-14867-z","article-title":"B38-CAP Is a Bacteria-Derived ACE2-Like Enzyme That Suppresses Hypertension and Cardiac Dysfunction","volume":"11","author":"Minato","year":"2020","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc0870","article-title":"Engineering Human ACE2 to Optimize Binding to the Spike Protein of SARS Coronavirus 2","volume":"369","author":"Chan","year":"2020","journal-title":"Science"},{"key":"B29","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1681\/ASN.2020101537","article-title":"A Novel Soluble ACE2 Variant With Prolonged Duration of Action Neutralizes SARS-Cov-2 Infection in Human Kidney Organoids","volume":"32","author":"Wysocki","year":"2021","journal-title":"J Am Soc Nephrol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.510461","article-title":"Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2","volume":"111","author":"Ferrario","year":"2005","journal-title":"Circulation"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2005.00675.x","article-title":"Effects of Renin-Angiotensin System Blockade on Renal Angiotensin-(1-7) Forming Enzymes and Receptors","volume":"68","author":"Ferrario","year":"2005","journal-title":"Kidney Int"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2006923","article-title":"Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19","volume":"382","author":"Mancia","year":"2020","journal-title":"N Engl J Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.120.16314","article-title":"Antihypertensive Drugs and COVID-19 Risk: A Cohort Study of 2 Million Hypertensive Patients","volume":"77","author":"Semenzato","year":"2021","journal-title":"Hypertension"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1101\/2021.01.26.21250511","article-title":"The Angiotensin Type 2 Receptor Agonist C21 Restores Respiratory Function in COVID19 - A Double-Blind, Randomized, Placebo-Controlled Phase 2 Trial","author":"Tornling","year":"","journal-title":"medRxiv"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.732690\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T05:17:07Z","timestamp":1640150227000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.732690\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,22]]},"references-count":34,"alternative-id":["10.3389\/fimmu.2021.732690"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.732690","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,22]]},"article-number":"732690"}}