Quantifying Renin-Angiotensin-System Alterations in COVID-19

Abstract

The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.

Keywords: ACE2; Angiotensin II; Angiotensin-(1-7); RAS dysregulation; RAS-targeting drugs; SARS-CoV-2; spike protein.

Figure 1

Schematic representation of systemic RAS. The peptides belonging to RAS (AngI, AngII, Ang-(1-5), Ang-(1-7), Ang-(1-9), AngIII, AngIV) are in light blue boxes; renin produced by juxtaglomerular kidney cells and angiotensinogen produced by the liver are in dark blue boxes; the enzymatic actors of RAS are in green boxes: angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), neprilysin (NEP), chymase (CHYM), cathepsin A (CAT$${}_{\mathrm{A}}$$), thimet oligopeptidase (TO), aminopeptidase A (APA), aminopeptidase N (APN) and prolyloligopeptidase (POP). AngII type 1 receptor (AT1R) is in a red box, with the classical AngII/AT1R axis indicated with a red arrow; the MAS receptor (MASR) is in a deep blue box with the counter-regulatory axis Ang-(1-7)/MASR indicated with a deep blue arrow. The RAS feedback loop is shown with orange arrows. SARS-CoV-2, which acts on ACE2 through the binding of its spike protein, is indicated in magenta.

Figure 2

Schematic representation of the two main RAS axes ACE/AngII/AT1R and ACE2/Ang-(1-7)/MASR in: (a) controls and (b,c) CoViD-19 patients with two possible dysregulated RAS scenarios.

Figure 3

Log-ratios between RAS components (ACE2, AngII and Ang-(1-7)) in COVID-19 patients and controls, with the estimated confidence intervals, for all the collected studies referenced by their reference number (see Table S1). The dashed lines represent the averages of the log-ratios weighted according to the number of patients analyzed in each study. On the y-axis, the reference to the study is mentioned.