Renin-Angiotensin-Aldosterone System

Since the discovery of renin in 1898 as a “pressor hormone” the renin-angiotensin aldosterone system (RAAS) has evolved into an increasingly complex, pleiotropic regulatory system affecting fluid and electrolyte balance; cell proliferation, hypertrophy, survival and death; cognition and neurodegeneration; promoting inflammation and fibrosis; exacerbating co-morbid diseases such as diabetes mellitus; and secondarily the actions of aldosterone, for which angiotensin peptides are the primary activator. The metabolic pathways by which the angiotensin peptides are produced and modified involve an ever-increasing number of enzymes, with an ever-increasing number of receptors mediating effects of the various angiotensin peptides, aldosterone; even those of renin and its precursor prorenin. Given the predominant pathophysiological actions of RAAS, several classes of drugs have been developed to counteract these morbidities; renin and angiotensin-converting enzyme (ACE or ACE-1) inhibitors, AT1 type angiotensin II receptor antagonists, and aldosterone receptor antagonists. With the discovery of multiple angiotensin receptor types came the recognition of a second, counterregulatory arm of the RAAS involving the AT2 type receptor, the enzyme ACE-2, Mas, and Mas-related G protein-coupled receptors (Mrgs). Drugs under development include AT2 receptor agonists, Mas agonists and ACE-2 activators. With the discovery that ACE-2 is the primary receptor by which SARS-CoV-1 and 2 infects cells, its role as a COVID-19 facilitator versus its role as a counterregulator of the RAAS, has initiated considerable scientific debate.