Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19—severe acute respiratory syndrome coronavirus 2—gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1–7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1–7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.

Concerns on the Specificity of Commercial ELISAs for the Measurement of Angiotensin (1–7) and Angiotensin II in Human Plasma

“…The current coronavirus disease 2019 (COVID-19) pandemic and the interaction of severe acute respiratory syndrome coronavirus 2 virus with the renin-angiotensin system to bind and internalize ACE2 (angiotensin-converting enzyme 2, EC 3.4.17.23) has underscored the need for accurate assessment of the renin-angiotensin system in severe acute respiratory syndrome coronavirus 2-infected patients, particularly those with underlying cardiovascular disease including hypertension, heart failure, and kidney disease. 1 , 2 Liu et al 3 initially reported that patients with COVID-19 had significantly elevated plasma levels of Ang II (angiotensin II) as compared to healthy patients and that plasma Ang II levels correlated with a greater viral load and reduced lung function in the patients with COVID-19. 3 This study used a sensitive ELISA to directly quantify Ang II in plasma that requires a small sample volume (50 µL) and obviates the need for prior sample extraction or enrichment.…”

Controversial Roles of the Renin Angiotensin System and Its Modulators During the COVID-19 Pandemic

“…Other potential explanations for discrepant results between laboratories include the major experimental difficulties associated with the biochemical assessment of the various components of the RAAS, due to the poor specificity of antibodies and of synthetic substrates or inhibitors of ACE2, and to the poor availability of the most accurate assays of ACE2 activity such as high-performance liquid chromatography/mass spectrometry, as reviewed elsewhere ( Chappell, 2016 ; Sparks et al, 2020 ).…”

“…However, as outlined above for studies on pharmacologically induced modifications of ACE2 expression, it is very important while interpreting these studies to carefully consider the limitations of the biochemical assays to quantify the components of the RAAS ( Chappell, 2016 ; Sparks et al, 2020 ; Chappell et al, 2021 ).…”

Between two storms, vasoactive peptides or bradykinin underlie severity of COVID‐19?

“…By now, it is well‐recognized that the entry of SARS‐CoV‐2 to the host cell is mediated by peptidase ACE2 (angiotensin converting enzyme 2 (Hoffmann et al, 2020)), which is an important member of the renin‐angiotensin system (RAS) primarily responsible for conversion of angiotensin II into angiotensin‐(1‐7) (Karamyan & Speth, 2007a; Xia & Lazartigues, 2010). This link between SARS‐CoV‐2 and ACE2 has led to many experimental and clinical studies to explore the potential alteration of the RAS function in this disease, extend understanding of the pathology and guide the use of RAS‐modulating drugs in COVID‐19 patients (Sparks et al, 2020; Speth, 2020). Notably, a smaller number of investigators have recognized the intricate association of another peptidergic system, that is, bradykinin or kallikrein‐kinin system, with the RAS within the context of COVID‐19 (Ghahestani et al, 2020; Roche & Roche, 2020; van de Veerdonk et al, 2020).…”

“…As for any disease, in case of COVID‐19 too, detailed understanding of pathogenic mechanisms is critical for development of new therapies. Hence, it is natural that researchers around the world have used various approaches to explore and understand the COVID‐19 morbidity (Sparks et al, 2020; Wang et al, 2020). Among these, arguably most notable are studies focusing on inflammatory mechanisms, pro‐inflammatory cytokines, and “cytokine storm,” since they are fundamentally associated with progression of the disease and mortality of COVID‐19 patients (Mahmudpour et al, 2020; Rossi et al, 2020).…”