Renin-Angiotensin-Aldosterone System: Friend or Foe-The Matter of Balance. Insight on History, Therapeutic Implications and COVID-19 Interactions
Abstract
Apart from RAAS inhibition, there are several future prospects for RAAS-based therapies in COVID-19. First, Mas receptor stimulation via inhibition of Ang 1-7 degradation or enhancement of its endogenous production by recombinant ACE2 is being studied in clinical trials in COVID-19 patients.
Second, ACE2 is assumed not only to exert anti-inflammatory actions due to Ang II conversion to Ang 1-7; sACE2 maintains its catalytic activity but loses its virus internalization capability, thus serving as a potential decoy for virus particles, preventing their binding to mACE2 and cellular invasion. Third, enhancement of the bioavailability of alamandine by ACE2-induced angiotensin A conversion or its external delivery might be another clue for its anti-inflammatory and anti-remodeling effects.
Fourth, the dual neprilysin/AT1 inhibitor sacubitril/valsartan increases atrial natriuretic peptide availability with anti-inflammatory action along with the blockade of the toxic Ang II effects, potentially attenuating the threat of an excessive immune response in COVID-19. Fifth, spironolactone downregulates the TIMPRSS2 protease, which is necessary for spike protein processing by SARS-CoV-2 in the host cell.
Spironolactone also inhibits furin, which promotes the virus cell entrance and pulmonary inflammation Sixth, AT2R agonists, such as compound 21 (C21), could compensate the reduced ACE2/Ang 1-7/Mas signaling and provide compensatory attenuation of the inflammatory storm, endothelial damage and clot formation in the lungs, heart and brain by stimulating AT2 or Mas receptor.