Figure 4.

SARS-CoV-2 in the RAAS pathway. Prostaglandins stimulate the release of pro-renin from juxtaglomerular cells. Pro-renin is cleaved to renin by kallikrein. Renin is also produced by activated mast cells. Renin transforms angiotensinogen into angiotensin I. ACE or mast cell chymase converts angiotensin I into angiotensin II, which binds AT₁R, and stimulates the production of aldosterone and subsequently IL-6. Aldosterone promotes renal distal tubular reabsorption of sodium, increasing blood pressure. In response to intravascular volume expansion, cells in the atrial wall release atrial natriuretic peptide (ANP), which down-regulates angiotensin II activity. Mononuclear leukocyte-derived aspartate decarboxylase (MLDAD) converts the octapeptide angiotensin II to another octapeptide, angiotensin A, which promotes the activation or AT₁R, or may generate the anti-inflammatory heptapeptide (seven amino acid) ligand, alamandine, via ACE2 activity. ACE2 also converts angiotensin II to angiotensin-(1-7), which is a ligand for both the Mas receptor and AT₂R involved in vasodilation and anti-inflammatory responses. Additional aminopeptidases convert angiotensin II into angiotensin III and IV. Angiotensin III can bind Mas and both angiotensin III and substance P activate MGRPRX2 on mast cells. A lack of ACE2 in RAAS due to SARS-CoV-2-induced degradation may suggest a benefit for intervention along the ACE/angiotensin II/AT₁R/aldosterone pathway. These may include renin inhibitors (Renin-i), AT₁R blockers (ARB), ACE inhibitors (ACEi), aldosterone blockers (ALDi), or diuretics.