Understanding the Renin-Angiotensin-Aldosterone-SARS-CoV-Axis: A Comprehensive Review

The Renin-angiotensin-aldosterone system (RAAS) helps regulate blood pressure, sodium reabsorption, inflammation, and fibrosis at steady state. System imbalance can lead to multiple disorders.

Angiotensin II (Ang II) is a potent vasoconstrictor derived from angiotensin I cleavage by ACE. It activates two receptors: type 1 (AT1) and type 2 Ang II receptor (AT2). AT1 activation promotes vasoconstriction and inflammation (increased pro-inflammatory cytokine production and membrane permeability) resulting in acute lung injury and ARDS, atherogenesis as well as insulin resistance and thrombosis mechanisms. AT2 activation (weakly expressed at steady state) promotes vasodilation, decreased platelet aggregation, and increased insulin action. ACE2 (highly expressed by pulmonary epithelial cells) converts Ang II into Angiotensin(1-7) (Ang-[1-7]), shown to exert protective effects on the lungs - an effect also observed following AT2 activation. ACE2 activation inhibits the Ang II/AT1 pathway. Thus, the RAAS can be schematized into two opposite self-regulating pathways: Ang II/AT1 and ACE2/Ang-(1-7). High level of ACE2 can be found in some pathological cases, especially cardiovascular diseases, resulting from a compensatory mechanism of self-regulation.

ACEs inhibit the formation of Ang II while ARA2s increase the level of Ang II. Excess of the latter can cause redirection to the ACE2 pathway. ARA2s has been shown more effective than ACEs in promoting the ACE2 pathway. In the context of a pathological condition, ACE and ARA2 would thus modulate an inappropriate response of RAAS and inhibit the pro-inflammatory effects of AT1.

For example, COPD treatment using ARA2 clinically improving patients' symptoms by decreasing inflammation, vascular permeability, and lung lesions. The benefits of ARA2 and ACE inhibitors have also been observed in ARDS patients.

In the context of viral infections, SARS-CoV spike protein S1 has been shown to bind to ACE2 to infect host cells, therefore inhibiting its activity while increasing that of Ang II, involved in inflammation and lung damage. Male has been shown to be at increase risk for COVID-19 infection, which could be explained by lower AT2 expression (protective pathway) compared to women, and ACE2 gene location on the X chromosome. In addition, overactivation of the Ang I/AT1 pathway and a decrease in ACE2 has been observed in cardiovascular diseases associated with a poorer prognosis in patients with COVID-19. Therefore, RAAS blockers could benefit COVID-19 patients, by reducing lung inflammation and inhibiting host cell invasion by the virus.