The Systemic Renin-Angiotensin System in COVID-19

Abstract

Introduction: SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the “alternative” (alt) renin-angiotensin system (RAS). ACE2 counteracts angiotensin II by converting it to potentially protective angiotensin 1-7.Methods: Using mass spectrometry, we assessed key metabolites of the classical RAS (angiotensins I–II) and alt-RAS (angiotensins 1-7 and 1-5) pathways as well as ACE and ACE2 concentrations in 159 patients hospitalized with COVID-19, stratified by disease severity (severe, n=76; non-severe, n=83). Plasma renin activity (PRA-S) was calculated as the sum of RAS metabolites. We estimated ACE activity using the angiotensin II:I ratio (ACE-S) and estimated systemic alt-RAS activation using the ratio of alt-RAS axis metabolites to PRA-S (ALT-S). We applied mixed linear models to assess how PRA-S and ACE/ACE2 concentrations affected ALT-S, ACE-S, and angiotensins II and 1-7.Results: Median angiotensin I and II levels were higher with severe versus non-severe COVID-19 (both p<0.05), demonstrating activation of classical RAS. The difference disappeared with analysis limited to patients not taking a RAS inhibitor. ALT-S in severe COVID-19 increased with time (days 1–6: 0.12; days 11–16: 0.22) and correlated with ACE2 concentration (r=0.831). ACE-S was lower in severe versus non-severe COVID-19 (p<0.001), but ACE concentrations were similar between groups and weakly correlated with ACE-S (r=0.232). In mixed linear models, renin activity most strongly predicted angiotensin II and 1-7 levels. ACE2 also predicted angiotensin 1-7 levels and ALT-S. No single factor or the combined model, however, could fully explain ACE-S.Conclusions: Angiotensin II was elevated in severe COVID-19 but markedly influenced by RAS inhibitors and driven by overall RAS activation. ACE-S was significantly lower with severe COVID-19 and did not correlate with ACE concentrations. A shift to the alt-RAS axis because of increased ACE2 could partially explain the relative reduction in angiotensin II levels.