{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T21:19:05Z","timestamp":1774387145490,"version":"3.50.1"},"reference-count":83,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T00:00:00Z","timestamp":1606694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","award":["PER"],"award-info":[{"award-number":["PER"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1\u20137 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.<\/jats:p>","DOI":"10.3390\/v12121367","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T10:26:12Z","timestamp":1606731972000},"page":"1367","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Modeling the Molecular Impact of SARS-CoV-2 Infection on the Renin-Angiotensin System"],"prefix":"10.3390","volume":"12","author":[{"given":"Fabrizio","family":"Pucci","sequence":"first","affiliation":[{"name":"Computational Biology and Bioinformatics, Universit\u00e9 Libre de Bruxelles, CP 165\/61, Roosevelt Ave. 50, 1050 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0423-1933","authenticated-orcid":false,"given":"Philippe","family":"Bogaerts","sequence":"additional","affiliation":[{"name":"Biosystems Modeling and Control, Universit\u00e9 Libre de Bruxelles, CP 165\/61, Roosevelt Ave. 50, 1050 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3810-7802","authenticated-orcid":false,"given":"Marianne","family":"Rooman","sequence":"additional","affiliation":[{"name":"Computational Biology and Bioinformatics, Universit\u00e9 Libre de Bruxelles, CP 165\/61, Roosevelt Ave. 50, 1050 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1473-3099(20)30120-1","article-title":"An interactive web-based dashboard to track COVID-19 in real time","volume":"20","author":"Dong","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/S0140-6736(20)30154-9","article-title":"A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster","volume":"395","author":"Chan","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0140-6736(20)30211-7","article-title":"Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study","volume":"395","author":"Chen","year":"2020","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A new coronavirus associated with human respiratory disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41591-020-0820-9","article-title":"The proximal origin of SARS-CoV-2","volume":"26","author":"Andersen","year":"2020","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jmv.25688","article-title":"The 2019-new coronavirus epidemic: Evidence for virus evolution","volume":"92","author":"Benvenuto","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","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":"ref_9","doi-asserted-by":"crossref","first-page":"270","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":"ref_10","doi-asserted-by":"crossref","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":"ref_11","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1007\/s00134-020-05985-9","article-title":"Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target","volume":"46","author":"Zhang","year":"2020","journal-title":"Intensive Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41421-020-0147-1","article-title":"Comparative genetic analysis of the novel coronavirus (2019-nCoV\/SARS-CoV-2) receptor ACE2 in different populations","volume":"6","author":"Cao","year":"2020","journal-title":"Cell Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding","volume":"395","author":"Lu","year":"2020","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.tem.2004.03.001","article-title":"ACE2, a new regulator of the renin\u2013angiotensin system","volume":"15","author":"Burrell","year":"2004","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1161\/01.RES.87.5.e1","article-title":"A novel angiotensin-converting enzyme\u2013related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9","volume":"87","author":"Donoghue","year":"2000","journal-title":"Circ. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"33238","DOI":"10.1074\/jbc.M002615200","article-title":"A human homolog of angiotensin- converting enzyme cloning and functional expression as a captopril-insensitive carboxypeptidase","volume":"275","author":"Tipnis","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"112","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":"ref_18","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/nm1267","article-title":"A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus\u2013induced lung injury","volume":"11","author":"Kuba","year":"2005","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nature02145","article-title":"Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus","volume":"426","author":"Li","year":"2003","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13054-017-1823-x","article-title":"A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome","volume":"21","author":"Khan","year":"2017","journal-title":"Crit. Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1161\/CIRCRESAHA.120.317015","article-title":"Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20th anniversary of the discovery of ACE2","volume":"126","author":"Gheblawi","year":"2020","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"905","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":"ref_23","unstructured":"(2020, February 27). NCT04287686. Recombinant Human Angiotensin-Converting Enzyme 2 (rhACE2) as a Treatment for Patients with COVID-19, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04287686."},{"key":"ref_24","unstructured":"(2020, April 03). NCT04332666. Angiotensin-(1,7) Treatment in COVID-19: The ATCO Trial (ATCO), Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/NCT04332666."},{"key":"ref_25","unstructured":"(2020, April 06). NCT04335786. Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04335786."},{"key":"ref_26","unstructured":"(2020, March 17). NCT04312009. Losartan for Patients with COVID-19 Requiring Hospitalization, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04312009."},{"key":"ref_27","unstructured":"(2020, March 17). NCT04311177. Losartan for Patients with COVID-19 Not Requiring Hospitalization, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04311177."},{"key":"ref_28","unstructured":"(2020, March 24). NCT04318418. ACE Inhibitors, Angiotensin II Type-I Receptor Blockers and Severity of COVID-19 (CODIV-ACE), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04318418."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1056\/NEJMoa2008975","article-title":"Renin\u2013angiotensin\u2013aldosterone system inhibitors and risk of Covid-19","volume":"382","author":"Reynolds","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1056\/NEJMoa2006923","article-title":"Renin\u2013angiotensin\u2013aldosterone system blockers and the risk of Covid-19","volume":"382","author":"Mancia","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_31","first-page":"e102","article-title":"Cardiovascular disease, drug therapy, and mortality in COVID-19","volume":"382","author":"Mehra","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1152\/physrev.00036.2005","article-title":"Physiology of local renin-angiotensin systems","volume":"86","author":"Paul","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_33","unstructured":"Raizada, M.K., Phillips, M.I., and Sumners, C. (1993). Cellular and Molecular Biology of the Renin-Angiotensin System, CRC Press."},{"key":"ref_34","unstructured":"Casarini, D.E., Arita, D.Y., Cunha, T.S., and Colucci, J.A. (2016). New Aspects of the Renin Angiotensin System in Cardiovascular and Renal Diseases, Bentham."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"R647","DOI":"10.1152\/ajpregu.00039.2013","article-title":"A model-based approach to investigating the pathophysiological mechanisms of hypertension and response to antihypertensive therapies: Extending the Guyton model","volume":"306","author":"Hallow","year":"2014","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.compchemeng.2017.03.027","article-title":"A pharmacokinetic\/pharmacodynamic model of ACE inhibition of the renin-angiotensin system for normal and impaired renal function","volume":"104","author":"Versypt","year":"2017","journal-title":"Comput. Chem. Eng."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.compchemeng.2018.02.009","article-title":"Modeling sex differences in the renin angiotensin system and the efficacy of antihypertensive therapies","volume":"112","author":"Leete","year":"2018","journal-title":"Comput. Chem. Eng."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.compbiomed.2018.11.002","article-title":"Sex-specific long-term blood pressure regulation: Modeling and analysis","volume":"104","author":"Leete","year":"2019","journal-title":"Comput. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1161\/hy1201.100589","article-title":"Role of the renin-angiotensin system in vascular diseases: Expanding the field","volume":"38","author":"Lorenzo","year":"2001","journal-title":"Hypertension"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1164\/rccm.201203-0411OC","article-title":"Dysregulated renin\u2013angiotensin\u2013aldosterone system contributes to pulmonary arterial hypertension","volume":"186","author":"Tu","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1161\/HYPERTENSIONAHA.118.11065","article-title":"Role of renin-angiotensin-aldosterone system activation in promoting cardiovascular fibrosis and stiffness","volume":"72","author":"Jia","year":"2018","journal-title":"Hypertension"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1161\/CIRCRESAHA.116.303587","article-title":"Hypertension: Renin\u2013angiotensin\u2013 aldosterone system alterations","volume":"116","author":"Roks","year":"2015","journal-title":"Circ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1124\/pr.59.3.3","article-title":"The intrarenal renin-angiotensin system: From physiology to the pathobiology of hypertension and kidney disease","volume":"59","author":"Kobori","year":"2007","journal-title":"Pharmacol. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/bph.12159","article-title":"ACE2, angiotensin-(1-7) and M as receptor axis in inflammation and fibrosis","volume":"169","author":"Silveira","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Povlsen, A.L., Grimm, D., Wehland, M., Infanger, M., and Kr\u00fcger, M. (2020). The vasoactive Mas receptor in essential hypertension. J. Clin. Med., 9.","DOI":"10.3390\/jcm9010267"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8258","DOI":"10.1073\/pnas.1432869100","article-title":"Angiotensin-(1\u20137) is an endogenous ligand for the G protein-coupled receptor Mas","volume":"100","author":"Santos","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1093\/ajh\/hpw121","article-title":"AT2 receptors: Potential therapeutic targets for hypertension","volume":"30","author":"Carey","year":"2017","journal-title":"Am. J. Hypertens."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/nrd873","article-title":"Drugs targeting the renin\u2013angiotensin\u2013aldosterone system","volume":"1","author":"Zaman","year":"2002","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1177\/1753944716642680","article-title":"Drug discovery in renin\u2013angiotensin system intervention: Past and future","volume":"10","author":"Williams","year":"2016","journal-title":"Ther. Adv. Cardiovasc. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1183\/09031936.03.00088102","article-title":"Evaluation of a quantitative real-time PCR for the detection of respiratory syncytial virus in pulmonary diseases","volume":"21","author":"Borg","year":"2003","journal-title":"Eur. Respir. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"m1443","DOI":"10.1136\/bmj.m1443","article-title":"Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: Retrospective cohort study","volume":"369","author":"Zheng","year":"2020","journal-title":"BMJ"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s00134-012-2803-x","article-title":"A universal definition of ARDS: The PaO2\/FiO2 ratio under a standard ventilatory setting\u2014a prospective, multicenter validation study","volume":"39","author":"Villar","year":"2013","journal-title":"Intensive Care Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1056\/NEJM200005043421806","article-title":"The acute respiratory distress syndrome","volume":"342","author":"Ware","year":"2000","journal-title":"New Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0014-5793(98)01145-4","article-title":"Angiotensinogen cleavage by renin: Importance of a structurally constrained N-terminus","volume":"436","author":"Williamson","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"F956","DOI":"10.1152\/ajprenal.00090.2007","article-title":"Novel sandwich ELISA for human angiotensinogen","volume":"293","author":"Katsurada","year":"2007","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"H137","DOI":"10.1152\/ajpheart.00618.2015","article-title":"Biochemical evaluation of the renin-angiotensin system: The good, bad, and absolute?","volume":"310","author":"Chappell","year":"2016","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"H10","DOI":"10.1152\/ajpheart.01277.2007","article-title":"Sex differences in circulating and renal angiotensins of hypertensive mRen. Lewis but not normotensive Lewis rats","volume":"295","author":"Pendergrass","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"H1171","DOI":"10.1152\/ajpheart.00897.2014","article-title":"Differences in angiotensin (1\u20137) between men and women","volume":"308","author":"Sullivan","year":"2015","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1161\/01.HYP.8.6.476","article-title":"Specific measurement of angiotensin metabolites and in vitro generated angiotensin II in plasma","volume":"8","author":"Nussberger","year":"1986","journal-title":"Hypertension"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1093\/ajh\/5.6.393","article-title":"Measurement of converting enzyme activity by antibody-trapping of generated angiotensin II: Comparison with two other methods","volume":"5","author":"Nussberger","year":"1992","journal-title":"Am. J. Hypertens."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1161\/01.HYP.33.3.850","article-title":"Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists","volume":"33","author":"Mazzolai","year":"1999","journal-title":"Hypertension"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1161\/hy0102.102293","article-title":"Angiotensin II Suppression in humans by the orally active renin inhibitor aliskiren (SPP100) comparison with enalapril","volume":"39","author":"Nussberger","year":"2002","journal-title":"Hypertension"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Heran, B.S., Wong, M.M., Heran, I.K., and Wright, J.M. (2008). Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors for primary hypertension. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD003823.pub2"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1161\/01.HYP.0000161880.59963.da","article-title":"Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension","volume":"45","author":"Doulton","year":"2005","journal-title":"Hypertension"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1093\/cvr\/cvaa078","article-title":"The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2","volume":"116","author":"Chen","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41368-020-0074-x","article-title":"High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa","volume":"12","author":"Xu","year":"2020","journal-title":"Int. J. Oral Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/s41591-020-0868-6","article-title":"SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes","volume":"26","author":"Sungnak","year":"2020","journal-title":"Nat. Med."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Liu, N., Hong, Y., Chen, R.G., and Zhu, H.M. (2020). High rate of increased level of plasma Angiotensin II and its gender difference in COVID-19: An analysis of 55 hospitalized patients with COVID-19 in a single hospital, WuHan, China. medRxiv.","DOI":"10.21203\/rs.3.rs-51770\/v1"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1007\/s11427-020-1643-8","article-title":"Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury","volume":"63","author":"Liu","year":"2020","journal-title":"Sci. China Life Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/s41577-020-0331-4","article-title":"Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages","volume":"20","author":"Merad","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s11906-018-0900-0","article-title":"Inflammation as a regulator of the renin-angiotensin system and blood pressure","volume":"20","author":"Satou","year":"2018","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1172\/JCI117809","article-title":"Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis","volume":"95","author":"Vaughan","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1111\/j.1538-7836.2005.01420.x","article-title":"PAI-1 and atherothrombosis","volume":"3","author":"Vaughan","year":"2005","journal-title":"J. Thromb. Haemost."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Ssentongo, A., Ssentongo, P., Heilbrunn, E.S., Lekoubou, A., Du, P., Liao, D., Oh, J.S., and Chinchilli, V.M. (2020). Renin-angiotensin-aldosterone system inhibitors and mortality in patients with hypertension hospitalized for COVID-19: A systematic review and meta-analysis. medRxiv.","DOI":"10.1101\/2020.05.21.20107003"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Khera, R., Clark, C., Lu, Y., Guo, Y., Ren, S., Truax, B., Spatz, E.S., Murugiah, K., Lin, Z., and Omer, S.B. (2020). Association of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers with the Risk of Hospitalization and Death in Hypertensive Patients with Coronavirus Disease-19. medRxiv.","DOI":"10.1101\/2020.05.17.20104943"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Baral, R., White, M., and Vassiliou, V.S. (2020). Impact of hospitalised patients with COVID-19 taking Renin-Angiotensin-Aldosterone System inhibitors: A systematic review and meta-analysis. medRxiv.","DOI":"10.1101\/2020.05.03.20089375"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40635-015-0044-3","article-title":"Angiotensin-(1-7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental Acute Respiratory Distress Syndrome","volume":"3","author":"Zambelli","year":"2015","journal-title":"Intensive Care Med. Exp."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/sj.jhh.1001022","article-title":"Chymase-dependent angiotensin II formation in human blood vessels","volume":"14","author":"Chester","year":"2000","journal-title":"J. Hum. Hypertens."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1517\/14656566.8.5.529","article-title":"Angiotensin II reactivation and aldosterone escape phenomena in renin\u2013angiotensin\u2013aldosterone system blockade: Is oral renin inhibition the solution?","volume":"8","author":"Athyros","year":"2007","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1465-9921-11-164","article-title":"Expression of neutral endopeptidase activity during clinical and experimental acute lung injury","volume":"11","author":"Hashimoto","year":"2010","journal-title":"Respir. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s11897-016-0292-x","article-title":"Neprilysin and natriuretic peptide regulation in heart failure","volume":"13","year":"2016","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Acanfora, D., Ciccone, M.M., Scicchitano, P., Acanfora, C., and Casucci, G. (2020). Neprilysin inhibitor\u2013angiotensin II receptor blocker combination (sacubitril\/valsartan): Rationale for adoption in SARS-CoV-2 patients. Eur. Heart-J.\u2013Cardiovasc. Pharmacother.","DOI":"10.1093\/ehjcvp\/pvaa028"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1681\/ASN.2016101066","article-title":"Immunologic effects of the renin-angiotensin system","volume":"28","author":"Crowley","year":"2017","journal-title":"J. Am. Soc. Nephrol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/12\/1367\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:39:29Z","timestamp":1760179169000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/12\/1367"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,30]]},"references-count":83,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["v12121367"],"URL":"https:\/\/doi.org\/10.3390\/v12121367","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,30]]}}}