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.

Highlights

  • Severe Acute Respiratory Syndrome (SARS)-CoV-2/human/Wuhan/X1/2019 was firstly described in December 2019, in Wuhan, China (Zhou et al, 2020)

  • The high affinity binding of Ang-(1-7) to the Mas receptor (MasR) is possible after the cleavage of Angiotensin II (Ang II) by Angiotensin-converting Enzyme 2 (ACE2), subtracting the Phenylalanine amino acid (Santos et al, 2018)

  • Discoveries on ACE2 and the MasR resulted in a new conception of the Renin Angiotensin System (RAS)

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Summary

Introduction

SARS-CoV-2/human/Wuhan/X1/2019 was firstly described in December 2019, in Wuhan, China (Zhou et al, 2020). From 1965, when the first coronavirus was identified in patients with common cold (Tyrrell and Bynoe, 1965) until now, seven coronaviruses are described to cause human diseases: HCoV-OC43, HKU1, HCoV-229E, HCoV-NL63, SARS-CoV, MERS-CoV, and SARS-CoV-2 (Wang Q. et al, 2020). These pathogens are zoonotic viruses that jumped species boundaries (Zhang and Holmes, 2020), leading to human diseases. The coronaviruses share the potential to outbreak as pandemics, but small and crucial genetic mutations directly influence their infectivity On this wise, viruses are obligate intracellular pathogens and their survival relies entirely on host cell machinery control to synthesize and organize their structural components. We show how the binding of SARS-CoV-2 may trigger a Renin Angiotensin System (RAS)

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