Two hits to the renin-angiotensin system may play a key role in severe COVID-19

Abstract

The spike glycoprotein on the virion surface docking onto the angiotensin-converting enzyme (ACE) 2 dimer is an essential step in the process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in human cells-involves downregulation of ACE2 expression with systemic renin-angiotensin system (RAS) imbalance and promotion of multi-organ damage. In general, the RAS induces vasoconstriction, hypertension, inflammation, fibrosis, and proliferation via the ACE/Ang II/Ang II type 1 receptor (AT1R) axis and induces the opposite effects via the ACE2/Ang (1-7)/Mas axis. The RAS may be activated by chronic inflammation in hypertension, diabetes, obesity, and cancer. SARS-CoV-2 induces the ACE2 internalization and shedding, leading to the inactivation of the ACE2/Ang (1-7)/Mas axis. Therefore, we hypothesize that two hits to the RAS drives COVID-19 progression. In brief, the first hit originates from chronic inflammation activating the ACE/Ang II/AT1R axis, and the second originates from the COVID-19 infection inactivating the ACE2/Ang (1-7)/Mas axis. Moreover, the two hits to the RAS may be the primary reason for increased mortality in patients with COVID-19 who have comorbidities and may serve as a therapeutic target for COVID-19 treatment.

Keywords: coronavirus disease 2019; renin-angiotensin system); two hits.

FIGURE 1

Steady‐state of the RAS under normal physiological conditions. The RAS signal transduction system is activated via the ACE/Ang II/AT1R axis; this promotes vasoconstriction, hypertension, inflammation, fibrosis, and proliferation. Studies on the biological functions of AT2R, a receptor of Ang II, are scant. Although AT2R activation induces the effects opposite to those of AT1R activation, AT2R expression is lower than AT1R expression in most adult tissues. Most functions of Ang II are performed via AT1R. The ACE2/Ang (1‐7)/Mas axis induces the opposite effects to suppress the harmful effects of the ACE/Ang II/AT1R axis induction

FIGURE 2

Two hits to the RAS by chronic inflammation and COVID‐19 infection. The ACE/Ang II/AT1R axis of the RAS is activated through chronic inflammation, including hypertension, diabetes, obesity, and cancer. Furthermore, SARS‐CoV‐2 induces ACE2 internalization and shedding, which lead to inactivation of the ACE2/Ang (1‐7)/Mas axis. Therefore, the two hits to the RAS may be the primary reason for the mortality rate being high among patients with COVID‐19 who have comorbidities. In brief, the first hit originates from chronic inflammation activating the ACE/Ang II/AT1R axis, and the second hit originates from the COVID‐19 infection inactivating the ACE2/Ang (1‐7)/Mas axis