COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system

• Published in: Nature communications Vol. 12; no. 1; p. 2417
• Main Authors: Rysz, Susanne, Al-Saadi, Jonathan, Sjöström, Anna, Farm, Maria, Campoccia Jalde, Francesca, Plattén, Michael, Eriksson, Helen, Klein, Margareta, Vargas-Paris, Roberto, Nyrén, Sven, Abdula, Goran, Ouellette, Russell, Granberg, Tobias, Jonsson Fagerlund, Malin, Lundberg, Johan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 59/57; 692/163/2743/348; 692/308/1426; 692/699/255/2514; ACE2; Aldosterone; Alveoli; Angiotensin; Angiotensin II; Angiotensin II - administration & dosage; Angiotensin II - metabolism; Angiotensin Receptor Antagonists - administration & dosage; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - antagonists & inhibitors; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Blood coagulation; Blood pressure; Coronaviruses; COVID-19; COVID-19 - metabolism; COVID-19 - physiopathology; COVID-19 - virology; Endocrine system; Female; Fysiologi; Heparin; Humanities and Social Sciences; Humans; Infektionsmedicin; Kardiologi; Klinisk medicin; Lung - diagnostic imaging; Lung - physiopathology; Lung - virology; Lungs; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; multidisciplinary; Necrosis; Oxygenation; Pathophysiology; Perfusion; Protein Binding - drug effects; Pulmonary arteries; Pulmonary artery; Receptors; Renin; Renin-Angiotensin System - physiology; Retrospective Studies; SARS-CoV-2 - isolation & purification; SARS-CoV-2 - metabolism; SARS-CoV-2 - physiology; Science; Science (multidisciplinary); Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - metabolism; Swine; Thromboembolism; Virus Internalization - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22713-z

SARS-CoV-2 uses ACE2, an inhibitor of the Renin-Angiotensin-Aldosterone System (RAAS), for cellular entry. Studies indicate that RAAS imbalance worsens the prognosis in COVID-19. We present a consecutive retrospective COVID-19 cohort with findings of frequent pulmonary thromboembolism (17%), high pulmonary artery pressure (60%) and lung MRI perfusion disturbances. We demonstrate, in swine, that infusing angiotensin II or blocking ACE2 induces increased pulmonary artery pressure, reduces blood oxygenation, increases coagulation, disturbs lung perfusion, induces diffuse alveolar damage, and acute tubular necrosis compared to control animals. We further demonstrate that this imbalanced state can be ameliorated by infusion of an angiotensin receptor blocker and low-molecular-weight heparin. In this work, we show that a pathophysiological state in swine induced by RAAS imbalance shares several features with the clinical COVID-19 presentation. Therefore, we propose that severe COVID-19 could partially be driven by a RAAS imbalance. The SARS-CoV-2 receptor ACE2 is involved in the Renin-Angiotensin-Aldosterone System (RAAS). Over-activation of RAAS in swine results in a disease state similar to that of COVID-19 in human patients, suggesting that COVID-19 pathophysiology may be driven, at least in part, by an imbalance of this hormonal system.