Figure 1.

Schematic diagram of the effects of RAAS system during SARS-CoV-2 infection and the proposed therapeutic treatment. (1) Renin secreted, by the kidney, cleaves angiotensinogen, produced by liver, to form AT1, (2) AT1 is converted to AT2 by pulmonary ACE. (3) AT2 binds to AT2R1 (Angiotensin II receptors 1). The excess of AT2 through AT2R1 hyperactivation causes vasoconstriction, sodium retention (by aldosterone release), hypertension, inflammatory, IL-6, hypertrophy, fibrosis, thrombosis. (4) SARS-CoV-2 binds to ACE2 to gain entry into the host cell, however, cellular protective response leads to ACE2 shedding. (5) ADAM17-regulated ectodomain shedding of ACE2 results in increased amount of soluble and active ACE2 (sACE2). (6) AT1 and AT2 can also bind to sACE2. (7) They are then metabolized by ACE2 into Ag 1–9 and Ag 1–7, respectively. (8) The excess of Ag 1–9 and Ag 1–7 signaling via the AT2R2 and MasR can induce vasodilatation, natriuresis, hypotension, anti-inflammatory, IL-10, lymphopenia, apoptosis, thrombosis. (9) These events, in turn, produce a compensatory upregulation of both renin secretion and ACE activity, which establish the onset of a positive feedback loop. In the black boxes, drugs that can potentially to stop the positive feedback loop, by inhibiting enzymes of the RAAS, are indicated. Dashed arrows indicate enzymatic activity, full arrows indicate non enzymatic passage and dashed blue arrows represent the positive feedback loop. Created in Biorender.com.