Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic

Abstract

The current COVID-19 pandemic is associated with unprecedented morbidity and mortality. Early reports suggested an association between disease severity and hypertension but did not account for sources of confounding. However, the responsible virus — SARS-CoV-2 — gains entry to host cells via angiotensin-converting enzyme 2 (ACE2), highlighting the need to understand the relationship between the virus and the renin–angiotensin system (RAS) and how this might be affected by RAS inhibitors.

Fig. 1. Possible effects of renin–angiotensin system inhibition on COVID-19.

The competing hypothetical mechanisms by which inhibition of the renin–angiotensin system (RAS) with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) might be harmful (upper panels) or protective (lower panels) in COVID-19. Hypothesis 1: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains entry into the cell by binding to angiotensin-converting enzyme 2 (ACE2; upper left panel). The addition of an ACEi or ARB could increase ACE2 abundance and thus enhance viral entry (upper right panel). Hypothesis 2: angiotensin II (Ang II) drives lung injury by activating the type 1 angiotensin receptor (AT1R), causing inflammation and fibrosis (lower left panel). Diminishing production of Ang II with an ACEi or blocking Ang II–AT1R actions with an ARB enhances the generation of Ang-(1–7) by ACE2 and activation of the Mas receptor (MasR), which attenuates inflammation and fibrosis and therefore attenuates lung injury.