EFFECTS OF ACE INHIBITORS AND ANGIOTENSIN TYPE-1 RECEPTOR BLOCKERS ON ACE-2 EXPRESSION IN HUMAN ALVEOLAR EPITHELIAL CELLS

Abstract

Objective: Angiotensin converting enzyme 2 (ACE-2) has regained widespread attention as the cellular receptor of SARS-CoV-2 virus that caused the COVID-19 pandemic. It was contended that ACE inhibitors (ACEis) and angiotensin type 1 receptor (AT1R) antagonists (ARBs) increase ACE2 expression in lung cells and their administration in Covid-19 patients could be detrimental and/or constitute a potential risk factor. As there were no evidences supporting this hypothesis we investigated the effect of ACEis/ARBs on ACE2 expression in lung cells. Design and method: Calu-3 cells, epithelial cells derived from lung adenocarcinoma, were treated with 10 μM irbesartan (ARB), or 10 μM ramipril (ACEi) alone or in the presence of 100 nM Angiotensin II (Ang II) for 12 hours in serum-free media. After 12 hrs ACE2 mRNA expression was evaluated by Digital droplet (dd)PCR. Results: We found that Ang II increased by two-fold ACE2 mRNA copies (vehicle 792.7 ± 161.3 vs Ang II 1475 ± 319.9; p < 0.001), while both irbesartan and ramipril did not affect ACE2 expression levels (722.3 ± 170.2 and 747.8 ± 313.8, respectively). Moreover, pretreatment with irbesartan abolished Ang II-induced ACE2 expression (722.3 ± 170.2 copies irbesartan vs 1046 ± 182.4 copies Ang II + irbesartan; p < 0.05), while pretreatment with rampiril had no such effect (1252 ± 246,4 copies Ang II + ramipril). Conclusions: ARBs and ACEis do not increase ACE2 expression at mRNA levels in human epithelial lung cells. Ang II increased ACE2 expression by acting via AT1R. Therefore, these results provided mechanistic support to a beneficial effect of both ACEi and ARB treatment in Covid19 patients with Sars-CoV-2 infection.