The renin angiotensin aldosterone system and COVID-19

Hadeel A Alsufyani, James R Docherty, Hadeel A Alsufyani, James R Docherty

Abstract

The ongoing pandemic has stimulated study of the Renin Angiotensin Aldosterone System (RAAS), and how it can be manipulated to treat COVID-19. Studies are examining whether drugs that act on the RAAS system might be useful to treat COVID-19. COVID-19 and the RAAS are closely linked both in infection and in possible post-infection inflammatory cascades. We detail the Physiology and Pharmacology of the RAAS including the effects of aldosterone and atrial natriuretic peptide. It is appropriate that the theoretical benefits of modulation of the RAAS should be considered based on available knowledge of the complexity of the system. In this short review we have tried to explain the actions of the angiotensin family of peptides and produce a relatively simple model and diagrammatic summary of the RAAS and the possible sites of intervention.

Keywords: Angiotensin; COVID-19; RAAS.

Conflict of interest statement

The authors declared that there is no conflict of interest.

© 2020 The Author(s).

Figures

Fig. 1
Fig. 1
The RAAS under normal conditions is a complex balance of pro- and anti-inflammatory mediators. For simplicity, some actions of agents are not indicated. The enzymes Renin, ACE1, ACE2 and aminopeptidases (AP) are displayed in small rectangles and receptors are displayed in small circles. Colour coding: red for generally pro-inflammatory pathways (arrows) and mediators, blue for generally anti-inflammatory pathways (arrows) and mediators. PRO indicates pro-inflammatory etc, ANTI indicates anti-inflammatory. Large rectangles show target tissues. Actions on cardiac atria are shown as stimulation or inhibition of atrial natriuretic peptide (ANP) secretion (due to the complexity of the diagram, ANP secretion is shown both top left and right). Actions on the zona glomerulosa of adrenal cortex are shown as aldosterone secretion. Actions shown on renal tubules are sodium (Na+) retention (aldosterone) and sodium (Na+) excretion (ANP). Widespread actions (PRO or ANTI) on multiple target tissues are Inflammation, vasoconstriction, proliferation, endothelial and pneumocyte dysfunction, etc. Background shading indicates: ACE1 products (pink); products requiring ACE2 alone or ACE2 and ACE1 (blue). Abbreviations: ANP, atrial natriuretic peptide; AP: aminopeptidases; AT1-R: AT1-receptor; AT2-R: AT2-receptor; AT4-R: AT4-receptor; mas-R: mas-receptor; MCR: mineralocorticoid receptor.
Fig. 2
Fig. 2
The relationship between the various angiotensin peptides.
Fig. 3
Fig. 3
The effects of Cov-2 virus on the RAAS. Cov-2 (CoV in yellow triangle) binds to ACE2, reducing the number of active ACE2 molecules. Thick arrows show diversion of precursors into the ACE1 product signalling pathways; thin arrows show diminished ACE2 product signalling pathways. The system is shifted towards pro-inflammatory pathways. Colour coding: red for generally pro-inflammatory pathways (arrows) and agents, blue for generally anti-inflammatory pathways (arrows) and agents. Abbreviations: ANP, atrial natriuretic peptide; AT1-R: AT1-receptor; AT2-R: AT2-receptor; AT4-R: AT4-receptor; CoV: Cov-2 virus bound to ACE2; mas-R: mas-receptor; MCR: mineralocorticoid receptor. For general description, see Fig. 1.
Fig. 4
Fig. 4
Possible sites of drug action in manpulating the RAAS system that may potentially reduce the effects of Cov-2. Numbers 1–7 in purple refer to numbered sections (5.1-5.7) of the text concerning potential sites of drug action. Abbreviations: ANP, atrial natriuretic peptide (ANP); AT1-R: AT1-receptor; AT2-R: AT2-receptor; AT4-R: AT4-receptor; CoV: Cov-2 virus bound to ACE2; mas-R: mas-receptor; MCR: mineralocorticoid receptor. For general description, see Fig. 1.

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