The Renin-Angiotensin System (RAS) in COVID-19 Disease: Where We Are 3 Years after the Beginning of the Pandemic

Abstract

The RAS is a hormonal system playing a pivotal role in the control of blood pressure and electrolyte homeostasis, the alteration of which is associated with different pathologies, including acute respiratory distress syndrome (ARDS). As such, it is not surprising that a number of studies have attempted to elucidate the role and balance of the renin-angiotensin system (RAS) in COVID-19. In this review article, we will describe the evidence collected regarding the two main enzymes of the RAS (i.e., ACE and ACE2) and their principal molecular products (i.e., AngII and Ang1-7) in SARS-CoV-2 infection, with the overarching goal of drawing conclusions on their possible role as clinical markers in association with disease severity, progression, and outcome. Moreover, we will bring into the picture new experimental data regarding the systemic activity of ACE and ACE2 as well as the concentration of AngII and Ang1-7 in a cohort of 47 COVID-19 patients hospitalized at the IRCCS Sacro Cuore-Don Calabria Hospital (Negrar, Italy) between March and April 2020. Finally, we will discuss the possibility of considering this systemic pathway as a clinical marker for COVID-19.

Keywords: ACE; ACE2; Ang1-7; AngII; COVID-19; RAS pathway.

Figure 1

Schematic representation of the classical and alternative RAS. The main enzymes, hormones, and peptide products of the system are reported, together with the main systemic and local effects mediated by the RAS. The two enzymes and the two products described in this review manuscript are highlighted in bold. AngI: angiotensin I; AngII: angiotensin II; Ang1-7: angiotensin 1-7; ACE: angiotensin converting enzyme; ACE2: angiotensin converting enzyme 2. This figure was created using Biorender.com.

Figure 2

(A) Plots showing ACE and ACE2 activities and Ang1-7 and AngII concentrations in COVID-19 patients (C-19) and healthy controls (non-C19). Dotted line represents the median, and error bars represent the interquartile range. Statistical comparisons were computed using the Mann–Whitney test. **** = p-value < 0.0001. (B) Spearman correlation matrix for ACE and ACE2 activities, and Ang1-7 and AngII concentrations in COVID-19 patients (C-19) and healthy controls (non-C19). Color scale represents Spearman rho coefficient. Stars on plot indicate statistically significant correlations. * = p-value < 0.05; ** = p-value < 0.005.

Figure 3

(A) Plots showing Ang1-7 concentrations and ACE2 activity in COVID-19 patients under ACEi/ARBs treatment (ACEi/ARBs) and COVID-19 patients not under ACEi/ARBs treatment (non- ACEi/ARBs). (B) Plots showing AngII concentrations and ACE2 activities in COVID-19 patients with comorbidities (comorbidity) and COVID-19 patients without comorbidities (non-comorbidity). Dotted line represents median, and error bars represent interquartile range. Statistical comparisons were computed using the Mann–Whitney test. * = p-value < 0.05; ** = p-value < 0.01.