The fight against COVID-19: Striking a balance in the renin-angiotensin system

Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by interacting with membrane-bound angiotensin-converting enzyme 2 (ACE2), a vital element in the renin-angiotensin system (RAS), which regulates blood pressure, fluid balance, and cardiovascular functions. We herein evaluate existing evidence for the molecular alterations within the RAS pathway (e.g., ACE2 and angiotensin II) during SARS-CoV-2 infection and subsequent Coronavirus Disease 2019 (COVID-19). This includes reports regarding potential effect of RAS blockade (e.g., ACE inhibitors and angiotensin II receptor blockers) on ACE2 expression and clinical outcomes in patients with co-morbidities commonly treated with these agents. The collective evidence suggests a dual role for ACE2 in COVID-19, depending on the stage of infection and the coexisting diseases in individual patients. This information is further discussed with respect to potential therapeutic strategies targeting RAS for COVID-19 treatment.

Keywords: Angiotensin II (Ang II); Angiotensin-converting enzyme 2 (ACE2); COVID-19; RAS blockade; Renin-angiotensin system (RAS); SARS-CoV-2.

Figure 1

Circulating renin–angiotensin system (RAS). RAS begins with angiotensinogen secretion from the liver and renin release from kidneys, stimulated by low blood arterial pressure and reduced sodium chloride levels. Renin converts angiotensinogen to angiotensin I (Ang I). Angiotensin-converting enzyme (ACE), expressed in endothelial cells of multiple organs, including those within the cardiovascular system, acts on Ang I to produce the principal pressor hormone angiotensin II (Ang II). Ang II interacts with the Ang II type 1 receptor (AT1R) to regulate a variety of effector functions, including vascular contraction, endothelial function, protein synthesis, fibrosis, hypertrophy, and inflammation. Alternatively, Ang II can also be cleaved by ACE2 to form angiotensin 1–7. The physiological functions of angiotensin 1–7 are mediated through the Mas receptor. These are beneficial responses that antagonize the harmful effects of Ang II/AT1R.

Figure 2

Angiotensin-converting enzyme 2 (ACE2) regulation. (a) ACE2 expression is regulated transcriptionally via apelin signaling and sirtuin 1 (SIRT1) activation in response to energy stress [e.g., hypoxia or AMP kinase (AMPK) activation], transcription modulators, such as miR-421 and miR-483-3p, and post-translational mechanisms that involve feedback signaling of angiotensin II (Ang II). Ang II binding to Ang II type 1 receptor (AT1R) generates reactive oxygen species (ROS), stimulating a disintegrin metalloproteinase 17 (ADAM17), which cleaves cell-surface ACE2 and activates several signaling cascades, such as MAPK and ERK1/2. (b) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated endocytosis might also result in downregulation of ACE2 surface expression , , , , .

Figure 3

Proposed dual role of renin–angiotensin system (RAS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and Coronavirus 2019 (COVID-19) progression. (a) The SARS-CoV-2 virus exploits the angiotensin-converting enzyme 2 (ACE2) receptor expressed on the cell-surface membrane as the initial host entry point. During the internalization process, the virus hijacks ACE2 through endocytosis and potentially activates receptor-shedding mechanisms. At the same time, soluble serum ACE2 may help scavenge SARS-CoV-2 in circulation. (b) SARS-CoV-2-driven downregulation of ACE2 leads to increased angiotensin II (Ang II) activity, which induces detrimental cellular conditions that can worsen severe COVID-19 outcome. (c) RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), might upregulate ACE2 expression, leading to robust SARS-CoV-2 host entry during early stages of infection. (d) However, continued use of these drugs during late stages of COVID-19 can help mitigate and restore virus induced decreases in ACE2 expression. This will shift the angiotensin balance towards the Ang 1–7/MasR axis, providing a protective effect. Depending on the stage of infection, the ACEI/ARB output signal might switch between detrimental and protective during COVID-19 progression .