The RAAS
Angiotensinogen, produced primarily by the liver, is cleaved by the kidney protease, renin, to form angiotensin I (Ang I), a circulating pro-signaling decapeptide. RAAS-targeted cells express angiotensin-converting enzyme (ACE) that cleaves two amino acids off Ang I to form angiotensin II (Ang II), which then binds to Ang II receptors (ATR). ATR activation increases blood pressure and cardiac output both directly and indirectly through increased aldosterone production. ACE2 is also a membrane-bound protease expressed by RAAS-targeted cells, but it cleaves both Ang I and Ang II, removing only one amino acid from each to form Ang 1-9 and Ang 1-7 respectively. Both peptides bind to the MAS1 receptor in the same RAAS-targeted cells to exert a counter-regulatory balancing effect. In the setting of chronic RAAS stress, up-regulated ACE2 expression exerts an ameliorating homeostatic effect. However, increased ACE2 expression enables enhanced SARS-CoV-2 tropism with repeated viral cycling until ACE2 is depleted, disrupting RAAS homeostasis. (2)
Inexplicably overlooked in COVID-19, Ang II downstream signaling involves aldosterone and its receptor, the mineralocorticoid receptor (MR). Aldosterone is an inflammatory steroid, produced mainly in the adrenal glands and adipose cells, that was first recognized as a sodium-retaining hormone. (5) Ang II and low sodium/increased potassium extracellular concentrations stimulate aldosterone secretion interactively, such that Ang II-mediated aldosterone secretion is augmented in the setting of low sodium or high potassium. (6) Aldosterone synthesis is also increased by adrenocorticotrophic hormone while atrial and brain natriuretic factors and the synthetic steroid, dexamethasone, suppress aldosterone production.