Renin–angiotensin system inhibition in COVID-19 patients: Friend or foe?

Host cell penetration of SARS-COV-2 is mediated by angiotensin-converting enzyme 2 (ACE2), which is expressed on the surface of epithelial cellslining the respiratory tract, cardiomyocytes, endothelial cells, and vascular smooth muscle cells (1). Animal experiments have revealed that expression and activity of ACE2 in various organs are increased with the administration of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) (2). Therefore, previous speculations suggested worse outcomes in patients with COVID-19 with the use of renin–angiotensin system (RAS) inhibitors (3). Although, there is no evidence that shows an association of ACEIs or ARBs with upregulation of ACE2 levels in human lung or cardiac tissues, higher urinary ACE2 levels documented in patients with hypertension treated with ARBs suggest that upregulation of ACE2 may also occur in humans (4, 5). These findings led to the hypothesis that RAS inhibition by means of ACEIs and ARBs may increase the risk of COVID-19 through upregulation of ACE2 and increase of viral load. ACE2 is a paralogue of ACE; however, they have opposite effects (6). ACE2 downregulates the RAS and acts as a deactivator of angiotensin II by converting it into angiotensin-(1–7) which has opposite properties to angiotensin II. Angiotensin II is an active peptide causing vasoconstriction, fibrosis, and inflammation by binding to angiotensin 1 receptor (AT1R). In contrast, angiotensin-(1–7) induces vasodilatation and shows antifibrotic and anti-inflammatory properties (7).