A pressor dose of angiotensin II has no influence on the angiotensin-converting enzyme 2 and other molecules associated with SARS-CoV-2 infection in mice

FASEB J. 2021 Mar;35(3):e21419. doi: 10.1096/fj.202100016R.

Abstract

In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cell-surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.

Keywords: ARB; COVID-19; SARS-CoV-2; angiotensin II; angiotensin-converting enzyme 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / genetics
  • ADAM17 Protein / metabolism
  • Angiotensin II / administration & dosage
  • Angiotensin II / pharmacology*
  • Angiotensin II Type 1 Receptor Blockers / administration & dosage
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Animals
  • COVID-19 / metabolism*
  • Furin / genetics
  • Furin / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Losartan / administration & dosage
  • Losartan / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • SARS-CoV-2*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Vasoconstrictor Agents / pharmacology

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Vasoconstrictor Agents
  • Angiotensin II
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, mouse
  • Furin
  • ADAM17 Protein
  • Adam17 protein, mouse
  • Losartan