Renin-Angiotensin System Implications in SARS-CoV-2 Pathogenesis

The renin-angiotensin system (RAS) orchestrates cardiovascular homeostasis through a balance between the classical axis—renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and the type 1 receptor (AT1R)—and the counter-regulatory axis centred on ACE2, angiotensin 1-7 (Ang 1-7) and the Mas receptor (MasR). SARS-CoV-2 exploits ACE2 as its entry receptor, triggering downregulation of membrane ACE2 and thereby skewing the RAS towards unopposed Ang II–AT1R signalling. This shift promotes vasoconstriction, inflammation, oxidative stress and thrombosis, contributing to lung injury, endothelial damage and multi-organ dysfunction. Comorbid states such as hypertension, diabetes and cardiovascular disease amplify these effects by baseline RAS dysregulation and heightened ACE2 expression in target tissues, correlating with more severe clinical courses. Therapeutic strategies under investigation include restoration of ACE2 expression via recombinant soluble ACE2, blockade of Ang II–AT1R signalling using widely used antihypertensives, and enhancement of Ang 1-7–MasR activity. Understanding the interplay between viral entry, ACE2 downregulation and RAS imbalance provides a mechanistic framework for both antiviral and organ-protective interventions, balancing antiviral efficacy with preservation of RAS-mediated tissue protection.

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Technical terms

Renin-Angiotensin System (RAS): A hormonal cascade regulating blood pressure, fluid balance and vascular tone through peptide mediators and their receptors.

Angiotensin-Converting Enzyme 2 (ACE2): A membrane-bound carboxypeptidase that converts Ang II to Ang 1-7 and serves as the entry receptor for SARS-CoV-2.

Angiotensin II (Ang II): A potent vasoconstrictor peptide that promotes inflammation and fibrosis via the AT1 receptor.

Angiotensin 1-7 (Ang 1-7): A vasodilatory and anti-inflammatory peptide generated by ACE2 that signals through the Mas receptor.

AT1 Receptor (AT1R): A G-protein-coupled receptor mediating the deleterious effects of Ang II, including vasoconstriction and pro-inflammatory signalling.

Mas Receptor (MasR): A G-protein-coupled receptor activated by Ang 1-7, counteracting Ang II–AT1R effects to protect tissues.

References

1. P21-activated kinase 1 (PAK1)-mediated cytoskeleton rearrangement promotes SARS-CoV-2 entry and ACE2 autophagic degradation. Signal Transduction and Targeted Therapy (2023).
2. Angiotensin-converting enzyme 2—at the heart of the COVID-19 pandemic. Cell (2023).
3. ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification. Journal of Biomedical Science (2023).
4. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Critical Care (2017).