The interacting physiology of COVID‐19 and the renin‐angiotensin‐aldosterone system: Key agents for treatment

Abstract

SARS‐CoV‐2 interacting with its receptor, angiotensin‐converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS‐CoV‐2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole‐body response to maintain tissue perfusion. Tissue and circulating renin‐angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang‐(1‐7) by the enzyme ACE2. Ang‐(1‐7) has effects that are contrary to Ang II‐AT1R mediated effects. Thus, destruction of ACE2 by SARS‐CoV‐2 results in loss of control of the pro‐inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS‐CoV‐2 that is responsible for the pathogenesis of COVID‐19.

“LONG COVID”—A hypothesis for understanding the biological basis and pharmacological treatment strategy

“…Alternately or additionally, the loss of ACE-2 enzyme activity and reduced synthesis of angiotensin 1-7 causes elevated levels of angiotensin 1-8 that binds to AT1 receptors on cells and this is also known to activate the NLRP3 inflammasome to cause cell death by pyroptosis in lung epithelium cells, endothelium, and cardiomyocytes. 30,31 These important findings of NLRP3 inflammasome and renin-angiotensin system (RAS) activation give a and cellular explanation for the proinflammatory cytokine storm and acute multi-organ failures widely reported in patients with severe COVID-19 infection as well as future directions for discovering drug candidates to block activation of the NLRP3 inflammasome (reviewed by Lumbers et al 32 ). But do they explain "LONG COVID" and suggest drug treatments, appropriate doses, and administration timing for this puzzling disorder?…”

“…As outlined by Head et al in this Journal 37 in many people, SARS‐CoV‐2 reaches the lungs causing an acute respiratory distress (ARDS) because the virus has a lethal action on infected alveoli that impairs oxygenation of blood. The virus then crosses the alveoli–blood barrier and because of the widespread cellular distribution of its target ACE‐2 results in other organs such as heart, liver, kidney, and CNS becoming infected, provoking an immune response and organ failure, covered in Lumbers et al 32 This can be fatal particularly in elderly adults with comorbidities such as hypertension, type 2 diabetes, and obesity 4 . The United States among others have reported that young adults with obesity are more likely to require hospitalization and develop more severe disease than non‐obese young adults, 6 consistent with the known increased distribution and activity of the renin–angiotensin system in obesity 38 .…”

Critical insights to COVID‐19 disease and potential treatments using a systems analysis approach that integrates physiology, pharmacology, and clinical pharmacology

“…In fact, as outlined by Lumbers et al in this Themed Review 5 it is critical in understanding the pathogenesis of COVID‐19 to be aware of the destruction of the ACE2 receptor induced by SARS‐CoV‐ 2 binding. ACE2 is a component of the renin–angiotensin system (RAS) which is classically viewed as a circulating endocrine system which through the actions of its major peptide, angiotensin II (Ang II) controls blood pressure and fluid and electrolyte homeostasis.…”

“…In contrast, lower respiratory tract infection does not favor SARS‐CoV‐2 self‐assembly at scale but critically drives COVID‐19 pathophysiology. It is this pathophysiology that is thoroughly explored by Lumbers et al 5 in their sequenced review.…”

“…Angiotensin-converting enzyme inhibitors (ACEi) block the formation of Ang II from Ang I. Angiotensin receptor blocking (ARB) drugs block the actions of Ang II via its AT1R.Additionally, the enzyme ACE 2, a homologue of ACE, has two critical actions in blocking Ang II which are also potential key targets for therapeutics development. First, it catabolizes Ang II to Ang(1)(2)(3)(4)(5)(6)(7) and in doing so, it produces Ang (-1-7) which has opposing effects on tissues, cells, biochemical pathways etc, to those produced by Ang II.Like ACE, ACE2 is widely distributed throughout almost every organ of the body and along the lining of blood vessels. Furthermore, ACE2 is a highly conserved protein having appeared early in evolution as it is found in chordates >100 million years ago.…”