Understanding the renin–angiotensin–aldosterone–SARS-CoV axis: a comprehensive review

Abstract

<jats:sec><jats:title>Importance</jats:title><jats:p>Coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin–angiotensin–aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin–angiotensin–aldosterone–SARS-CoV (RAAS–SCoV) axis. There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS–SCoV axis (informed by prior studies of SARS-CoV), how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner.</jats:p></jats:sec><jats:sec><jats:title>Observations</jats:title><jats:p>This review discusses the role of the RAAS–SCoV axis in acute lung injury and the effects, risks and benefits of pharmacological modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favour a protective effect of RAAS–SCoV axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remain limited.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Proposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiological effects caused by the virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS–SCoV axis on acute lung injury in COVID-19.</jats:p></jats:sec>

RAAS inhibitors are not associated with mortality in COVID-19 patients: Findings from an observational multicenter study in Italy and a meta-analysis of 19 studies

“…This tissue distribution is consistent with the pathophysiology and clinical features of SARS infection and related disease [3]. ACE2 is a key modulator of the renin-angiotensin-aldosterone system (RAAS), which is a signaling pathway involved in the regulation of vascular and heart function [4].…”

“…RAAS blockers were, however, also hypothesized to exert protective effects [4]. Indeed, recombinant ACE2 or losartan might counteract both pulmonary edema and the reduced lung function due to decreased expression of ACE2 [9,10].…”

The Role and Therapeutic Potential of NF-kappa-B Pathway in Severe COVID-19 Patients

“…This was shown as a major factor in the higher case-fatality rates associated with SARS and MERS, when compared to COVID-19 (Wit et al 2016 ). The increase in angiotensin II (AngII) caused by reduced level of angiotensin converting enzyme II (ACE2) membrane protein which is endocytosed along with n-CoV has been implicated in the progression of lung injury and propagation of severe inflammation due to dysregulation of renin-angiotensin pathway (RAS) (Ingraham et al 2020 ). AngII acts as a proinflammatory cytokine via angiotensin-1-receptor (AT1R), the latter also activates NF-κB, disintegrin and metalloprotease 17 (ADAM17) (Devaux et al 2020 ).…”

Can Hyperperfusion of Nonaerated Lung Explain COVID-19 Hypoxia?

“…The virus is known to enter cells via the ACE2 receptor, and may potentially interfere with the renin-angiotensin system in ways that alter pulmonary vascular tone 12 . Although it is reported that later stages of the disease are characterized by downregulation of ACE2 and vasoconstriction (promoting ARDS) [12][13][14] , it is possible that earlier stages instead promote local vasodilation or impairment of HPV 5,15 flow is equal to the fraction of lung with impaired oxygen transport (Fshu:Finj = 1). Heterogeneous 162 perfusion may increase the risk for larger Fshu, especially when the injured region also receives more baseline perfusion (see Figure 2).…”