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In general, the RAS induces vasoconstriction, hypertension, inflammation, fibrosis, and proliferation via the ACE\/Ang II\/Ang II type 1 receptor (AT1R) axis and induces the opposite effects via the ACE2\/Ang (1\u20107)\/Mas axis. The RAS may be activated by chronic inflammation in hypertension, diabetes, obesity, and cancer. SARS\u2010CoV\u20102 induces the ACE2 internalization and shedding, leading to the inactivation of the ACE2\/Ang (1\u20107)\/Mas axis. Therefore, we hypothesize that two hits to the RAS drives COVID\u201019 progression. In brief, the first hit originates from chronic inflammation activating the ACE\/Ang II\/AT1R axis, and the second originates from the COVID\u201019 infection inactivating the ACE2\/Ang (1\u20107)\/Mas axis. Moreover, the two hits to the RAS may be the primary reason for increased mortality in patients with COVID\u201019 who have comorbidities and may serve as a therapeutic target for COVID\u201019 treatment.<\/jats:p>","DOI":"10.1002\/kjm2.12237","type":"journal-article","created":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T16:51:20Z","timestamp":1591203080000},"page":"389-392","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Two hits to the renin\u2010angiotensin system may play a key role in severe <scp>COVID<\/scp>\u201019"],"prefix":"10.1002","volume":"36","author":[{"given":"Yu\u2010Hsin","family":"Tseng","sequence":"first","affiliation":[{"name":"Department of Pediatrics Kaohsiung Medical University Hospital, Kaohsiung Medical University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rei\u2010Cheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kaohsiung Medical University Hospital, Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Graduate Institute of Medicine, College of Medicine Kaohsiung Medical University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzong\u2010Shi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Renal Division Brigham and Women's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.317015"},{"key":"e_1_2_8_3_1","unstructured":"World Health Organization (WHO). 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