Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System

Abstract

The emergence of SARS-CoV-2/human/Wuhan/X1/2019, a virus belonging to the species Severe acute respiratory syndrome-related coronavirus, and the recognition of Coronavirus Disease 2019 (COVID-19) as a pandemic have highly increased the scientific research regarding the pathogenesis of COVID-19. The Renin Angiotensin System (RAS) seems to be involved in COVID-19 natural course, since studies suggest the membrane-bound Angiotensin-converting enzyme 2 (ACE2) works as SARS-CoV-2 cellular receptor. Besides the efforts of the scientific community to understand the virus' molecular interactions with human cells, few studies summarize what has been so far discovered about SARS-CoV-2 signaling mechanisms and its interactions with RAS molecules. This review aims to discuss possible SARS-CoV-2 intracellular signaling pathways, cell entry mechanism and the possible consequences of the interaction with RAS components, including Angiotensin II (Ang II), Angiotensin-(1-7) [Ang-(1-7)], Angiotensin-converting enzyme (ACE), ACE2, Angiotensin II receptor type-1 (AT1), and Mas Receptor. We also discuss ongoing clinical trials and treatment based on RAS cascade intervention. Data were obtained independently by the two authors who carried out a search in the PubMed, Embase, LILACS, Cochrane, Scopus, SciELO and the National Institute of Health databases using Medical Subject Heading terms as "SARS-CoV-2," "COVID-19," "Renin Angiotensin System," "ACE2," "Angiotensin II," "Angiotensin-(1-7)," and "AT1 receptor." Similarly to other members of Coronaviridae family, the molecular interactions between the pathogen and the membrane-bound ACE2 are based on the cleavage of the spike glycoprotein (S) in two subunits. Following the binding of the S1 receptor-binding domain (RBD) to ACE2, transmembrane protease/serine subfamily 2 (TMPRSS2) cleaves the S2 domain to facilitate membrane fusion. It is very likely that SARS-CoV-2 cell entry results in downregulation of membrane-bound ACE2, an enzyme that converts Ang II into Ang-(1-7). This mechanism can result in lung injury and vasoconstriction. In addition, Ang II activates pro-inflammatory cascades when binding to the AT1 Receptor. On the other hand, Ang-(1-7) promotes anti-inflammatory effects through its interactions with the Mas Receptor. These molecules might be possible therapeutic targets for treating COVID-19. Thus, the understanding of SARS-CoV-2 intracellular pathways and interactions with the RAS may clarify COVID-19 physiopathology and open perspectives for new treatments and strategies.

Keywords: ACE2; AT1 receptor; Ang II; Ang-(1-7); COVID-19; Renin Angiotensin System; SARS-CoV-2; pathogenesis.

FIGURE 1

Potential mechanisms of SARS-CoV-2 Spike glycoprotein (S) binding to and invading host cell. (A) Virion gets closer to the host cell that expresses a high-affinity binding receptor on its surface. In its native fusion-competent state, the Spike glycoprotein (S) of SARS-CoV-2 is anchored on the virion envelope. (B) S is formed by a S1 subunit, which contains the receptor-binding domain (RBD), and by a S2 subunit, comprising the fusion peptide (FP) domain. (C) Two of the most important proteins in the host cell surface related to the virus entry are Angiotensin-converting Enzyme 2 (ACE2) and Transmembrane protease/serine subfamily 2 (TMPRSS2); (D) Membrane bound-ACE2 is the SARS-CoV-2 receptor, and TMPRSS2 is the S primer. These two host cell proteins probably form a complex on the lipid bilayer; (E) S1 RBD attaches to ACE2 and TMPRSS2 cleaves S2 in a step named as priming, leading to the exposure of the FP; (F) Viral S protein is anchored not only to virion surface, but also to host plasma membrane. Hence, other S is recruited and the endocytic viral entry process begins. These are representative no-scale images.

FIGURE 2

The proposed role of the Renin-Angiotensin System in the pathophysiology of COVID-19. Schematic representation of COVID-19 pathophysiology related to the Renin-Angiotensin System (RAS) imbalance. This figure highlights the downregulation of transmembrane Angiotensin-converting enzyme 2 (ACE2) in SARS-CoV-2 infection. The virus enters the host cell after binding to TMPRSS2 and transmembrane ACE2. Viral replication and release from lung cells to the bloodstream enhance viremia, besides diminishing circulating and transmembrane ACE2 levels. The reduction of ACE2 availability results in RAS imbalance due to downregulation of the alternative axis. Consequently, we have an increase in Angiotensin II (Ang II) and decrease in Angiotensin-(1-7) [Ang-(1-7)] levels. The binding of Ang II to the Angiotensin II type 1 (AT1) receptor triggers inflammatory response, including vascular leakage and alveolar edema, both of which can be amplified by Cytokine Storm Syndrome (CSS). This mechanism may contribute to several clinical presentations of COVID-19, including respiratory signs and symptoms. In addition, the downregulation of the ACE2/Ang-(1-7)/Mas receptor axis reduces the anti-inflammatory effects of the alternative RAS axis. Due to ACE2 expression in mature lymphocytes, SARS-CoV-2 may result in lymphopenia. This finding can also be triggered by hemophagocytic lymphohistiocytosis (HLH) due to intense tissue inflammation. In addition, the invasion of the bone marrow by the virus, specifically of the hematopoietic stem/progenitor cells (HSPC), leads to apoptosis and consequent reduction of oxygen saturation levels. Other mechanisms that may contribute to lower saturation include vascular leakage, alveolar edema and inflammation. ACE2, Angiotensin Converting Enzyme 2; TMPRSS2, Transmembrane protease serine 2; RAS, Renin-Angiotensin-System; ANGII, Angiotensin II; ANG(1-7), Angiotensin (1-7); HLH, Hemophagocytic Lymphohistiocytosis; HSPC, Hematopoietic stem/progenitor cell; [O2], Oxygen concentration; ACE, Angiotensin Converting Enzyme; ANG(1-9), Angiotensin (1-9); ANGI, Angiotensin I; PEP, prolyl-endopeptidase; NEP, neutral-endopeptidase.