ACE2, the Counter-Regulatory Renin-Angiotensin System Axis and COVID-19 Severity

Angiotensin (ANG)-converting enzyme (ACE2) is an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). ACE2 also contributes to a deviation of the lung renin-angiotensin system (RAS) towards its counter-regulatory axis, thus transforming harmful ANG II to protective ANG (1-7). Based on this purported ACE2 double function, it has been put forward that the benefit from ACE2 upregulation with renin-angiotensin-aldosterone system inhibitors (RAASi) counterbalances COVID-19 risks due to counter-regulatory RAS axis amplification. In this manuscript we discuss the relationship between ACE2 expression and function in the lungs and other organs and COVID-19 severity. Recent data suggested that the involvement of ACE2 in the lung counter-regulatory RAS axis is limited. In this setting, an augmentation of ACE2 expression and/or a dissociation of ACE2 from the ANG (1-7)/Mas pathways that leaves unopposed the ACE2 function, the SARS-CoV-2 entry receptor, predisposes to more severe disease and it appears to often occur in the relevant risk factors. Further, the effect of RAASi on ACE2 expression and on COVID-19 severity and the overall clinical implications are discussed.