{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T23:33:56Z","timestamp":1772580836643,"version":"3.50.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007479","name":"Fondazione Cassa di Risparmio di Padova e Rovigo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007479","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>COVID-19 is spreading globally with the angiotensin converting enzyme (ACE)-2 serving as the entry point of SARS-CoV-2 virus. This raised concerns how ACE2 and the Renin-Angiotensin (Ang)-System (RAS) are to be dealt with given their roles in hypertension and their involvement in COVID-19's morbidity and mortality. Specifically, increased ACE2 expression in response to treatment with ACE inhibitors (ACEi) and Ang II receptor blockers (ARBs) might theoretically increase COVID-19 risk by increasing SARS-CoV-2 binding sites. However, ACE2 is part of the protective counter-regulatory ACE2-Ang1-7-MasR axis, which opposes the classical ACE-AngII-AT1R regulatory axis. We used Gitelman's and Bartter's syndromes (GS\/BS) patients, rare genetic tubulopathies that have endogenously increased levels of ACE2, to explore these issues. Specifically, 128 genetically confirmed GS\/BS patients, living in Lombardia, Emilia Romagna and Veneto, the Northern Italy hot spots for COVID-19, were surveyed <jats:italic>via<\/jats:italic> telephone survey regarding COVID-19. The survey found no COVID-19 infection and absence of COVID-19 symptoms in any patient. Comparison analysis with the prevalence of COVID-19 in those regions showed statistical significance (<jats:italic>p<\/jats:italic> &amp;lt; 0.01). The results of the study strongly suggest that increased ACE2 does not increase risk of COVID-19 and that ACEi and ARBs by blocking excessive AT1R-mediated Ang II activation might favor the increase of ACE2-derived Ang 1-7. GS\/BS patients' increased ACE2 and Ang 1-7 levels and their characteristic chronic metabolic alkalosis suggest a mechanism similar to that of chloroquine\/hydroxychloroquine effect on ACE2 glycosylation alteration with resulting SARS-COV-2 binding inhibition and blockage\/inhibition of viral entry. Studies from our laboratory are ongoing to explore GS\/BS ACE2 glycosylation and other potential beneficial effects of BS\/GS. Importantly, the absence of frank COVID-19 or of COVID-19 symptoms in the BS\/GS patients cohort, given no direct ascertainment of COVID-19 status, suggest that elevated ACE2 levels as found in GS\/BS patients at a minimum render COVID-19 infection asymptomatic and thus that COVID-19 symptoms are driven by ACE2 levels.<\/jats:p>","DOI":"10.3389\/fmed.2021.647319","type":"journal-article","created":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T05:14:20Z","timestamp":1620105260000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["ACE2 and SARS-CoV-2 Infection Risk: Insights From Patients With Two Rare Genetic Tubulopathies, Gitelman's and Bartter's Syndromes"],"prefix":"10.3389","volume":"8","author":[{"given":"Lorenzo A.","family":"Cal\u00f2","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Rigato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Sgarabotto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Gianesello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Bertoldi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verdiana","family":"Ravarotto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul A.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e21","DOI":"10.1016\/S2213-2600(20)30116-8","article-title":"Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?","volume":"8","author":"Fang","year":"2020","journal-title":"Lancet Respir Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1002\/ddr.21656","article-title":"Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics","volume":"81","author":"Gurwitz","year":"2020","journal-title":"Drug Dev Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/s41569-019-0244-8","article-title":"Counter-regulatory renin\u2013angiotensin system in cardiovascular disease","volume":"17","author":"Paz Ocaranza","year":"2020","journal-title":"Nat Rev Cardiol"},{"key":"B4","first-page":"472","article-title":"ACE2 and angiotensin 1-7 are increased in a human model of cardiovascular hyporeactivity: pathophysiological implications","volume":"23","author":"Cal\u00f2","year":"2010","journal-title":"J Nephrol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1097\/HJH.0000000000000321","article-title":"Understanding the mechanisms of angiotensin II signaling involved in hypertension and its long-term sequelae: insights from Bartter's and Gitelman's syndromes, human models of endogenous angiotensin II signaling antagonism","volume":"32","author":"Cal\u00f2","year":"2014","journal-title":"J Hypertens"},{"key":"B6","unstructured":"Dipartimento della Protezione Civile"},{"key":"B7","doi-asserted-by":"publisher","first-page":"175","DOI":"10.23750\/abm.v91i3-S.9511","article-title":"COVID-19 in Italy: impact of containment measures and prevalence estimates of infection in the general population","volume":"91","author":"Signorelli","year":"2020","journal-title":"Acta Biomed"},{"key":"B8","article-title":"R: A Language and Environment for Statistical Computing","year":"2020"},{"key":"B9","unstructured":"INPS"},{"key":"B10","unstructured":"Doxa2020"},{"key":"B11","doi-asserted-by":"publisher","first-page":"239","DOI":"10.3389\/fmed.2020.00239","article-title":"Official data and analytical forecasts: differences and similarities among coronavirus disease (COVID-19) confirmed cases and deaths","volume":"7","author":"Ferraro","year":"2020","journal-title":"Front Med"},{"key":"B12","article-title":"Version April 26, 2020","year":"2020"},{"key":"B13","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13293-020-00304-9","article-title":"Impact of sex and gender on COVID-19 outcomes in Europe","volume":"11","author":"Gebhard","year":"2020","journal-title":"Biol Sex Differ"},{"key":"B14","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1038\/s42003-020-1088-9","article-title":"Sex differences in SARS-CoV-2 infection rates and the potential link to prostate cancer","volume":"3","author":"Chakravarty","year":"2020","journal-title":"Commun Biol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e30","DOI":"10.1016\/S2213-2600(20)30153-3","article-title":"Antihypertensive Drugs and Risk of COVID-19?","volume":"8","author":"Tignanelli","year":"2020","journal-title":"Lancet Respir Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1161\/01.HYP.0000196268.08909.fb","article-title":"Angiotensin-converting enzyme 2 and angiotensin-(1\u20137): an evolving story in cardiovascular regulation","volume":"47","author":"Ferrario","year":"2006","journal-title":"Hypertension"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1161\/HYPERTENSIONAHA.106.084848","article-title":"Angiotensin-(1-7) counterregulates angiotensin II in human endothelial cells","volume":"50","author":"Sampaio","year":"2007","journal-title":"Hypertension"},{"key":"B18","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1097\/MNH.0b013e32831b70ad","article-title":"Angiotensin-converting enzyme 2: implications for blood pressure and kidney disease","volume":"18","author":"Ingelfinger","year":"2009","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"B19","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1002\/jmv.25785","article-title":"Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19","volume":"92","author":"Cheng","year":"2020","journal-title":"J Med Virol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"104736","DOI":"10.1016\/j.phrs.2020.104736","article-title":"Acute lung injury: the therapeutic role of Rho kinase inhibitors","volume":"155","author":"Abedi","year":"2020","journal-title":"Pharmacol Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.thromres.2019.02.016","article-title":"RhoA-Rho associated kinase signaling leads to renin-angiotensin system imbalance and angiotensin converting enzyme 2 has a protective role in acute pulmonary embolism","volume":"176","author":"Xu","year":"2019","journal-title":"Thromb Res"},{"key":"B22","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1097\/HJH.0b013e328010d4d2","article-title":"RhoA\/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans","volume":"25","author":"Cal\u00f2","year":"2007","journal-title":"J Hypertens."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.3390\/jcm9051328","article-title":"ROCK (RhoA\/Rho Kinase) in cardiovascular-renal pathophysiology: a review of new advancements","volume":"9","author":"Seccia","year":"2020","journal-title":"J Clin Med"},{"key":"B24","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1097\/HJH.0000000000000075","article-title":"Increased level of p63RhoGEFand RhoA\/Rho kinase activity in hypertensive patients","volume":"32","author":"Cal\u00f2","year":"2014","journal-title":"J Hypertens"},{"key":"B25","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/1743-422X-2-69","article-title":"Chloroquine is a potent inhibitor of SARS coronavirus infection and spread","volume":"2","author":"Vincent","year":"2005","journal-title":"Virol J"},{"key":"B26","doi-asserted-by":"publisher","first-page":"807","DOI":"10.2174\/1871530320666200427112902","article-title":"Focus on receptors for coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target - a perspective","volume":"20","author":"Magrone","year":"2020","journal-title":"Endocr Metab Immune Disord Drug Targets"},{"key":"B27","doi-asserted-by":"publisher","first-page":"5660","DOI":"10.3390\/ijms21165660","article-title":"Are the clinical presentations (phenotypes) of Gitelman's and Bartter's syndromes gene mutations driven by their effects on intracellular pH, their pH enotype?","volume":"21","author":"Cal\u00f2","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B28","doi-asserted-by":"publisher","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":"B29","doi-asserted-by":"publisher","first-page":"eabb5676","DOI":"10.1126\/scitranslmed.abb5676","article-title":"An ACE therapy for COVID-19","volume":"12","author":"Rodell","year":"2020","journal-title":"Sci Transl Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1681\/ASN.2020050640","article-title":"Possible protective effect of renin-angiotensin system inhibitors in COVID-19 induced acute kidney injury","volume":"31","author":"Kow","year":"2020","journal-title":"J Am Soc Nephrol"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.647319\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T05:14:25Z","timestamp":1620105265000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.647319\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":30,"alternative-id":["10.3389\/fmed.2021.647319"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.647319","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,4]]},"article-number":"647319"}}