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.