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

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.