Angiotensin II Promotes SARS-CoV-2 Infection via Upregulation of ACE2 in Human Bronchial Cells

Blockers of the renin-angiotensin system (RAS) have been reported to increase the angiotensin converting enzyme (ACE)2, the cellular receptor of SARS-CoV-2, and thus the risk and course of COVID-19. Therefore, we investigated if angiotensin (Ang) II and RAS blockers affected ACE2 expression and SARS-CoV-2 infectivity in human epithelial bronchial Calu-3 cells. By infectivity and spike-mediated cell-cell fusion assays, we showed that Ang II acting on the angiotensin type 1 receptor markedly increased ACE2 at mRNA and protein levels, resulting in enhanced SARS-CoV-2 cell entry. These effects were abolished by irbesartan and not affected by the blockade of ACE-1-mediated Ang II formation with ramipril, and of ACE2- mediated Ang II conversion into Ang 1-7 with MLN-4760. Thus, enhanced Ang II production in patients with an activated RAS might expose to a greater spread of COVID-19 infection in lung cells. The protective action of Angiotensin type 1 receptor antagonists (ARBs) documented in these studies provides a mechanistic explanation for the lack of worse outcomes in high-risk COVID-19 patients on RAS blockers.

Automated summary

Blockers of the renin-angiotensin system (RAS) can increase the expression of ACE2, the cellular receptor of SARS-CoV-2, and thus increase the risk of COVID-19. This study found that angiotensin II (Ang II) significantly increased the levels of ACE2 expression by acting on the angiotensin type 1 receptor, resulting in enhanced viral entry into cells. However, the blockade of ACE-1-mediated Ang II formation and ACE2-mediated Ang II conversion did not have any effect. Therefore, increased production of Ang II in patients with an activated RAS may lead to a greater spread of COVID-19 infection in lung cells.