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

Nat Commun. 2021 Apr 23;12(1):2417. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / administration & dosage
  • Angiotensin II / metabolism
  • Angiotensin Receptor Antagonists / administration & dosage
  • Angiotensin-Converting Enzyme 2 / antagonists & inhibitors
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • COVID-19 / metabolism
  • COVID-19 / physiopathology*
  • COVID-19 / virology
  • Female
  • Humans
  • Lung / diagnostic imaging
  • Lung / physiopathology*
  • Lung / virology
  • Magnetic Resonance Imaging / methods
  • Protein Binding / drug effects
  • Renin-Angiotensin System / physiology*
  • Retrospective Studies
  • SARS-CoV-2 / isolation & purification*
  • SARS-CoV-2 / metabolism
  • SARS-CoV-2 / physiology
  • Spike Glycoprotein, Coronavirus / metabolism
  • Swine
  • Virus Internalization / drug effects


  • Angiotensin Receptor Antagonists
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin II
  • Angiotensin-Converting Enzyme 2