Does Angiotensin II Peak in Response to SARS-CoV-2?

Léder Leal Xavier, Paula Fernanda Ribas Neves, Lisiê Valeria Paz, Laura Tartari Neves, Pamela Brambilla Bagatini, Luís Fernando Saraiva Macedo Timmers, Alberto Antônio Rasia-Filho, Régis Gemerasca Mestriner, Andrea Wieck, Léder Leal Xavier, Paula Fernanda Ribas Neves, Lisiê Valeria Paz, Laura Tartari Neves, Pamela Brambilla Bagatini, Luís Fernando Saraiva Macedo Timmers, Alberto Antônio Rasia-Filho, Régis Gemerasca Mestriner, Andrea Wieck

Abstract

Human infection by the SARS-CoV-2 is causing the current COVID-19 pandemic. With the growing numbers of cases and deaths, there is an urgent need to explore pathophysiological hypotheses in an attempt to better understand the factors determining the course of the disease. Here, we hypothesize that COVID-19 severity and its symptoms could be related to transmembrane and soluble Angiotensin-converting enzyme 2 (tACE2 and sACE2); Angiotensin II (ANG II); Angiotensin 1-7 (ANG 1-7) and angiotensin receptor 1 (AT1R) activation levels. Additionally, we hypothesize that an early peak in ANG II and ADAM-17 might represent a physiological attempt to reduce viral infection via tACE2. This viewpoint presents: (1) a brief introduction regarding the renin-angiotensin-aldosterone system (RAAS), detailing its receptors, molecular synthesis, and degradation routes; (2) a description of the proposed early changes in the RAAS in response to SARS-CoV-2 infection, including biological scenarios for the best and worst prognoses; and (3) the physiological pathways and reasoning for changes in the RAAS following SARS-CoV-2 infection.

Keywords: Angiotensin-converting enzyme 2; COVID-19; SARS-CoV-2; angiotensin-II; immune activation; immune response.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Xavier, Neves, Paz, Neves, Bagatini, Timmers, Rasia-Filho, Mestriner and Wieck.

Figures

Figure 1
Figure 1
The roles of the RAAS in health and COVID-19: A better and worse scenarios—(A) Basal angiotensin system. Figure representing the classic RAAS pathway. Angiotensin I (ANG I) is produced from angiotensinogen by renin. ANG I is converted to Angiotensin II (ANG II) by Angiotensin-Converting Enzyme (ACE). ANG II exerts its actions by binding to AT1R. Angiotensin-Converting Enzyme 2 (ACE2), is responsible for converting ANG I to Angiotensin 1-9 (ANG 1-9) and ANG II to Angiotensin 1-7 (ANG 1-7). ANG 1-7 has opposite effects to ANG II, counterbalancing ANG II physiological outcome. ADAM 17 and TPMRSS2 are sheddases responsible for cleaving tACE2 into its soluble form, sACE2. ADAM17 cleaves tACE2 in a constitutively manner, while TMPRSS2 is implicated in SARS-CoV-2 infection, supporting virus entry the cell host. (B) COVID-19 Best Scenario (for a better understanding, follow the order of numbers). Increased TMPRSS2 activity due to viral entry resulting in reduced tACE2 and consequent increase in sACE2, unable to convert ANG II in ANG 1-7. This will lead to increased ANG II levels, and increased AT1R activation, resulting in higher ADAM-17 activity. Higher ADAM-17 activity will increase biologically active sACE2 levels, able to convert ANG II in ANG 1-7, resulting in no alteration in ANG 1-7 levels. In this scenario, the intense tACE2 cleavage promoted by ANG II/AT1R/ADAM-17 axis will reduce virus entry into the cells. (C) COVID-19 Worst Scenario Note that this scenario is closely related to an incapacity in promote the ANG II peak or AT1R down-regulation, as suggested to the use of ACE inhibitors, genetic factors (i.e. A blood type), diabetes mellitus and cardiovascular diseases. (for a better understanding, follow the order of numbers). Increased TMPRSS2 activity due to viral entry resulting in a mild reduction tACE2 as well as a mild increase in sACE2, unable to convert ANG II into ANG 1-7. Consequently, ANG II levels will remain equal or even decrease, as well as AT1R activation, and resulting in ANG 1-7 decrease. In this scenario, the equal or low levels of ANG II, AT1R, and ADAM-17 activities will be associated to a mild decrease in tACE2 and a substantial increase in sACE2 produced by TPMRSS2, increasing the virus entry into the cells.
Figure 2
Figure 2
Summary of proposed changes in the RAAS, and downstream effects following SARS-CoV-2 infection. In the best-case scenario, a peak of ANG II occurs immediately after SARS-CoV-2 infects the cell. The virus reduces tACE2 levels due to increased TMPRSS2 and ADAM-17 activity. Reduced tACE2 levels decrease virus entry into the cell, and, consequently, the viral load. The ANG II peak will also increase AT1R activation, modulating not only the ANG II effects, but also the host immune response, which produces TNF-α and IFN-γ in an appropriate time and amount, favoring better clinical outcomes. In the worst-case scenario, the host is unable to elevate ANG II levels. Even with reduced tACE2 due to virus TMPRSS2 activation, ANG II levels remain unaltered or reduced. Consequently, ADAM-17 activation is lower or unaltered, thus, more tACE2 is available, allowing more virus to enter the cell and replicate. Moreover, AT1R activation is also low or unaltered, which leads to an inappropriate early immune response, favoring poor clinical outcomes.
Figure 3
Figure 3
Angiotensin II and T lymphocytes activation during COVID-19 best scenario. (A) 1: Reduction in tACE2 following SARS-CoV-2 infection. 2: ANG II will increase and 3: act as a co-stimulatory molecule in T lymphocytes activation acting via AT1R, which are expressed in CD8+ cells. 4: ANG II is also expressed by T lymphocytes, enhancing AT1R activation in an autocrine and intracrine manner. 5:AT1R activation stimulates CD8+ cells to produce both TNF-α and IFN-γ. 6: TNF-α will increase TH1 differentiation, and, together with IFN-γ, activate the inflammatory response. 7: TNF- α will also activate ADAM-17 activity leading to 8: increase the biologically active sACE2 and, 9: maintaining ANG 1-7 levels. 10: ANG 1-7, which has anti-inflammatory characteristics, will counterbalance TNF-α and IFN-γ direct effects via MasR pathway. Taken together, these alterations would lead to a proper immune response to SARS-CoV-2 infection. (B) Angiotensin II and T lymphocytes activation during COVID-19 worse scenario. 1: tACE2 levels are reduced following SARS-CoV-2 infection. 2: ANG II levels remain the same or are even low (see Figure 1C, COVID-19 Worse Scenario), 3: maintaining the AT1R activation in CD8+ cells at normal levels. 4: As a result, IFN-γ and TNF-α levels remain the same, 5: affecting the beginning of inflammatory response. 6: ADAM-17 activity is equal or reduced, 7: leading to reduced biologically active sACE2 levels. 8: consequently, ANG 1-7 levels are reduced. 9: This unbalanced immune response could not be adequate to combat SARS-CoV-2 infection.

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Source: PubMed

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