The Renin-Angiotensin System: A Key Role in SARS-CoV-2-Induced COVID-19

Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin–angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)–angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.

Angiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases

“…In the cardiovascular system (CV) system, AT1R overactivity has been associated with the development of several pathological conditions, including hypertension, vascular inflammation, atherosclerosis, and heart failure [ 55 , 56 ]. Furthermore, Ang II–AT1R binding activates many cascades in the vasculature, such as protein tyrosine phosphatases, NADPH oxidase, MAPK, and NO synthase, resulting in the expression of proinflammatory mediators, contraction, and endothelial dysfunction [ 57 , 58 ]. When AT1R is stimulated, NF-κB is activated, causing resident cells and endothelial cells to upregulate proinflammatory and procoagulant factors.…”

“…On the other hand, ACE2 counterbalances Ang II–AT1R effects by either stimulating an alternative pathway for Ang I degradation to produce Ang-(1–9), or by inactivating Ang II and hydrolyzing it to a heptapeptide Ang-(1–7). The latter stimulates vasodilation and activates anti-inflammatory, antifibrotic, and antithrombotic cascades via the MasR axis [ 59 , 60 ], as well as the protection of endothelial cell activity [ 57 , 58 ].…”

The Renin-Angiotensin System as a Component of Biotrauma in Acute Respiratory Distress Syndrome

“…Several studies have shown considerable association between ACE genotype (as observed with variable prevalence in different ethnic populations) and various disease endpoints such as sepsis, ARDS ( Pabalan et al, 2021 ), and risk of pneumonia ( Nie et al, 2014 ). In the context of COVID-19, there may also be a connection between frequency of ACE genotypes in populations and severity and outcome of this disease ( El-Arif et al, 2021 ). Furthermore, single-nucleotide polymorphisms in the ACE2 gene on chromosome Xp22.2 have been discussed as possible predetermining factors for COVID-19 severity.…”

“…The best-characterized ACE2 polymorphism is the splice region variant (rs2285666, G > A, Intron 3/4), which has also been shown to be associated with hypertension, coronary heart disease and diabetes with cerebral stroke ( Mohlendick et al, 2021 ). Other ACE2 polymorphisms may affect ACE2-spike protein binding affinity or binding of the co-factor TMPRSS2 that is needed for viral cell entry ( El-Arif et al, 2021 ; Suryamohan et al, 2021 ). In a study including hospitalized patients with COVID-19 age, high soluble ACE2 levels, a low aldosterone to renin ratio and the TMPRSS2 rs2070788 non-AA genotype were factors that independently predicted disease severity ( Akin et al, 2021 ).…”

The Time Has Come to Understand the Mechanisms by Which Comorbidities Contribute to COVID-19 Severity

“…SARS-CoV-2 decreases the effects of bradykinin 2-receptor as it affects bradykinin synthesis by inhibiting cathepsin L, present at the site of infection and involved in bradykinin production. Dysregulation of the renin-angiotensin-aldosterone balance and overactivation of angiotensin II type-I receptor axis could result in vasoconstriction and induction of the pro-fibrotic, apoptotic, and inflammatory signalizations in SARS-CoV-2-targeted tissues [21].…”