Effects of Renin-Angiotensin Inhibition on ACE2 (Angiotensin-Converting Enzyme 2) and TMPRSS2 (Transmembrane Protease Serine 2) Expression
Congqing Wu, Dien Ye, Adam E. Mullick, Zhenyu Li, A.H. Jan Danser, Alan Daugherty, Hong Lü
Abstract
A CE2 (angiotensin-converting enzyme 2) degrades Ang (an- giotensin) I and II and is a cellular receptor for severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019 (COVID-19).Viral entry into host cells occurs through binding of the viral spike (S) protein and ACE2. 1 Preclinical data suggest that renin-angiotensin system (RAS) blockers upregulate ACE2. 2,3As a consequence, RAS blockers have been suggested to increase the risk of developing severe acute respiratory syndrome coronavirus 2 infection.However, recent large retrospective studies strongly argue against this hypothesis and rather suggest that RAS blockers be protective in such patients. 4 Since the findings on RAS blocker-induced ACE2 upregulation are inconsistent, and differed not only per type of RAS inhibitors (ACE inhibitors versus ARB [angiotensin receptor blockers]), 3 between blockers of a certain type (ie, between various ARBs), but also per organ, and required high doses, one further option is that this ACE2 upregulation is not the unavoidable consequence of RAS suppression, but rather reflects the nonspecific effects of a certain RAS blocker when applied at a high dose.Applying antisense oligonucleotides (ASO) as a tool to suppress the RAS would circumvent the latter.In the present study, we determined effects of an ACE inhibitor (enalapril) and an ARB (losartan) as well as AGT (angiotensinogen) ASO on tissue ACE2 in male C57BL/6J mice.After 14 days of infusion, both enalapril and losartan increased plasma renin, measured as direct concentrations, by over 100-fold, confirming effective RAS inhibition (Figure [A]).ACE2 mRNA abundance was determined by quantitative PCR in lung, ileum, kidney, and heart tissues.Neither enalapril nor losartan changed the abundance of ACE2 mRNA in any of the tissues (Figure [B]).Ferrario et al 3 reported that administration of lisinopril (an ACE inhibitor) or losartan for