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Sabatier, J.; Fajloun, Z.; , .; Harb, J.; Annweiler, C.; Wu, Y.; Cao, Z.; De Neurophysiopathologie, I.; Abi Khattar, Z. Angiotensin II Type I Receptor (AT1R). Encyclopedia. Available online: https://encyclopedia.pub/entry/21637 (accessed on 08 July 2024).
Sabatier J, Fajloun Z,  , Harb J, Annweiler C, Wu Y, et al. Angiotensin II Type I Receptor (AT1R). Encyclopedia. Available at: https://encyclopedia.pub/entry/21637. Accessed July 08, 2024.
Sabatier, Jean-Marc, Ziad Fajloun,  , Julien Harb, Cedric Annweiler, Yingliang Wu, Zhijian Cao, Institut De Neurophysiopathologie, Ziad Abi Khattar. "Angiotensin II Type I Receptor (AT1R)" Encyclopedia, https://encyclopedia.pub/entry/21637 (accessed July 08, 2024).
Sabatier, J., Fajloun, Z., , ., Harb, J., Annweiler, C., Wu, Y., Cao, Z., De Neurophysiopathologie, I., & Abi Khattar, Z. (2022, April 12). Angiotensin II Type I Receptor (AT1R). In Encyclopedia. https://encyclopedia.pub/entry/21637
Sabatier, Jean-Marc, et al. "Angiotensin II Type I Receptor (AT1R)." Encyclopedia. Web. 12 April, 2022.
Angiotensin II Type I Receptor (AT1R)
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This entry is adapted from the peer-reviewed paper 10.3390/molecules27072048

AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II–AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.

SARS-CoV-2 COVID-19 Ang II–AT1R axis ACE2 AT1R downstream signaling pathways

1. Introduction

The physiological effects of Ang II are mediated mainly by AT1R and Ang II type 2 receptor (AT2R) [1][2][3]. AT1R effects include control of blood pressure, contraction of blood vessels, electrolyte balance, aldosterone synthesis and release from the adrenal cortex [4][5]. Furthermore, each receptor transmits opposing effects, with AT1R mediating vasoconstriction, proliferation, fibrosis, and inflammation and AT2R mediating vasodilation, antifibrosis, and anti-inflammation (Figure 1) [1][3]. AT1R and AT2R are G protein-coupled receptors (GPCRs) sharing a sequence identity of ~30% but having the same affinity for Ang II, which is their main ligand [3][6]. It has been shown that Ang II binding to the AT1R is involved in the pathophysiology of many different tissues. In fact, extreme Ang II–AT1R signaling induces the promotion of vascular remodeling and initiates the progression of atherosclerosis by producing endothelial dysfunction. Activation of AT1Rs in cardiomyocytes generates cellular hypertrophy, while binding of Ang II to AT1Rs on the surface of cardiac fibroblasts results in cardiac fibrosis by stimulating the synthesis of extracellular matrix proteins [7]. Moreover, findings demonstrated that activation of AT1R promotes the release of Ang II induced ROS, inflammation, and angiogenesis via the activation of several signaling pathways including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), extracellular signal-regulated kinases, (ERK1/2), mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription 1 (STAT1) pathways [8][9]. Unbalanced AT1R signaling in the lungs is associated with airway inflammation, bronchial hyper-responsiveness, fibrosis, and pulmonary hypertension [10][11].
The COVID-19 pandemic has prompted researchers to look for viable treatments, including vaccinations, antiviral medications that target the SARS-CoV-2 virus, and methods to manage disease pathology and complications caused by interactions with host components. Presently, 46.6% of the world population has been fully vaccinated [12]. However, it has been also shown that the treatment with RAS component inhibitors may have positive effects in treating COVID-19 diseases [13]. The most commonly used drugs include renin inhibitors, ACE inhibitors (ACEIs), and AT1R blockers (ARBs) [2]. ACEIs and ARBs have been shown to improve pulmonary capillary permeability, reduce apoptosis, and attenuate acute lung injury following SARS-CoV-2 infection [13]. In addition, ARBs might attenuate ARDS and cytokine storms in COVID-19 [14]. ARBs are nonpeptide antagonists, which include antihypertensive drugs such as losartan, olmesartan, candesartan, telmisartan, valsartan, irbesartan, eprosartan and azilsartan. These ARBs are now extensively used for treating cardiovascular diseases (CVDs), including heart failure, hypertension, cardiac hypertrophy, and arrhythmia [2]. ARBs block the binding of Ang II to the AT1R, thus making it available for the AT2R by turning off the vasoconstrictive, proliferative, and inflammatory effects [15]. Therefore, the significant clinical effectiveness of RAS blockers, together with their benefits for target organs, provides evidence of the continued clinical importance of RAS-targeted drug development [7].

2. AT1R Blockers (ARBs)

ARBs, a well-known antihypertensive drug group that blocks AT1R, have been postulated as tentative pharmacological agents to treat COVID-19-induced lung inflammation [16]. Therefore, it is common for individuals with hypertension to use ARBs in order to control their blood pressure. As its name suggests, this type of medication works by blocking the Ang II receptor, given its role in promoting the constriction of blood vessels and in increasing blood pressure [17][18]. Since these receptors are found in the heart, blood vessels, kidneys, and intestine [19][20], blocking their action helps in lowering blood pressure and preventing kidney and heart damage [21]. In addition, blocking AT1R may reduce acute lung injury and the response of inflammatory mediators [22].
There is a debate on the use of RAS inhibitors such as ARBs and ACEi in SARS-CoV-2 infection [23]. The role of these drugs in SARS-CoV-2 infection is unclear (Table 1).
Table 1. Summary of clinical studies and trials associated with hypertension and Ang II type 1 receptor blocker (ARB) administration in relation to COVID-19 infection.
Antihypertensive Drugs Used (% of Population) Period of ARB Intake before COVID-19 Infection Main Outcomes References
ARBs (48%) ≥7 days after hospital admission ARB treatment did not worsen clinical outcomes during COVID-19 infection in hypertensive patients. [24]
ARBs (50.6%) Not mentioned Previous administration of ARBs had no association with the number of days alive and out of the hospital in mild COVID-19. [25]
ARBs (31.34%) ≥1 week before the onset of infection ARB administration, before the onset of infection, significantly lowered the mortality rate in COVID-19 patients. [26]
ARBs (49.3%) Not mentioned ARB administration had no effect on the severity and mortality of COVID-19. [27]
ARBs (40.5%) For >1 y ARB administration improved clinical outcomes of COVID-19 patients with hypertension. [28]
ARBs (31.8%) Not mentioned ARBs were not associated with the severity or mortality of COVID-19 patients with hypertension. [29]
ARB (30.8%) ≥1 month before hospital admission ARB administration reduced the risk of death during hospitalization in COVID-19 hypertensive patients. [24]
ARBs (51%) ≥3 months before study conduction ARB administration lowered the risk of hospitalization and intubation or death with COVID-19; long-term use of ARBs might decrease the risk of COVID-19 in hypertensive patients. [30]
ARBs (29.7%) Unknown Administration of ARBs did not affect the chance of recovery in COVID-19 patients with hypertension or heart failure. [31]
ARBs (17%) Not mentioned Previous use of ARBs reduced the risk of mortality in patients hospitalized with COVID-19 infection. [32]
Some researchers speculated that RAS inhibitors would contribute to a higher susceptibility and severity of SARS-CoV-2 infection due to observations that elderly patients with CVD, for whom ARBs and ACEi are routinely prescribed, were at a higher risk for more severe SARS-CoV-2 infection [33][34]. Moreover, selected experimental studies suggested that RAS inhibitors may increase ACE2 expression [35][36][37]. On the other hand, many other studies contradicted such claims and implied that RAS inhibitors are effective in SARS-CoV-2 patients. ARBs are then believed to reduce acute lung injury in SARS-CoV-2 viral illness by the following mechanisms [16][38][39][40][41][42]: (1) blockade of AT1R may reduce the detrimental effects of Ang-II; (2) administration of ARBs may increase ACE2 expression, which may reduce the detrimental effects of Ang-II [23]; (3) AT1R blockade at the cell surface may reduce the internalization of the virus and consequently limit the decrease in ACE2 caused by the infection [23][43].
Soleimani et al. investigated the impact of ARBs on hospitalized hypertensive patients (48%) and found that they did not worsen clinical outcomes after COVID-19 infection [24]. Additionally, Meng et al. showed that ARB administration for 1 year before COVID-19 infection improved clinical outcomes of COVID-19 patients with hypertension (40.5%) [28]. Previous administration of ARBs had no association with the number of days alive and out of the hospital in mild COVID-19 patients (50.6%) [25]. Imai et al. used particular ARBs to treat acid-induced acute lung damage in ACE2 mutant mice. The pharmacological suppression of AT1R was found to reduce the severity of lung injury [44]. Gabriel et al. reviewed the effect of different ARBs on ACE2 and AT1R expression and investigated whether treatment of permissive ACE2+/AT1R+ Vero E6 cells with ARBs alters SARS-CoV-2 replication in vitro in an Ang II-free system. Azilsartan, eprosartan, irbesartan, and telmisartan induced a higher expression of ACE2 in Vero E6 cells than in untreated cells, which also have increased expression of AT1R, the binding of which to these blocking molecules was reduced. Interestingly, there are significant differences in the ability of ARBs to induce the overexpression of ACE2 once bound to AT1R, since some drugs at 7 µM (e.g., telmisartan) led to higher ACE2 increase than others when used at higher concentration (e.g., irbesartan at 60 µM) [21]. It is also known that following Ang II binding, AT1R triggers ACE2 cleavage and shedding, dependent on the p38–MAPK pathway, resulting in reduced cell surface expression [45][46]. In this regard, azilsartan, candesartan, losartan, and telmisartan have previously been demonstrated to have opposing effects on the MAPK pathway, which would preclude ACE2 excision [47][48].
The production of SARS-CoV-2 particles in supernatant of ARB-pretreated infected Vero E6 cells was evaluated at 24, 48, and 72 h.p.i. An increase in viral RNA expression in 24 h.p.i was significant for three of the ARBs used—azilsartan, eprosartan, and irbesartan. Interestingly, these compounds were likewise effective, positive modulators of the ACE2 protein expression. Moreover, the expression of viral proteins was evaluated inside of cells infected with SARS-CoV-2 after treatment with ARBs. These same three compounds were shown to induce the expression of S-protein, thus confirming the evidence that these compounds increase the multiplication of SARS-CoV-2. Results indicated that Vero E6 cells previously treated with ARBs for 72 h exhibit relative increases in ACE2 expression and SARS-CoV-2 production. Interestingly, scientists commented that Vero E6 cells were treated with ARBs without adding Ang II, which has been reported as a biomarker of severe COVID-19 [21]. In addition, increased SARS-CoV-2 production found in Vero E6 cells was not observed in the preliminary investigations recently performed on two human cell lines—namely, Caco-2 (intestinal epithelia origin) and Calu-3 (lung epithelia origin). It was suggested that one of the possible reasons for this is the low expression of AT1R in human lung tissues, compared with that in other organs such as the kidneys [21][49]. Scientists suggested that a broader spectrum of human cell lines must be examined to see if an acceptable human cellular model could be found in which ARBs could upregulate ACE2 expression and SARS-CoV-2 production [21].
Conversano et al. sought to describe patient characteristics, ongoing pharmacological treatment at the time of admission, and any link between chronic usage of ACE inhibitors/ARBs and negative COVID-19 clinical outcomes in 191 patients. Data demonstrated that chronic treatment with ACE inhibitors/ARBs did not result in increased mortality, worse clinical presentation, or impairment of renal function in pneumonia patients who were hospitalized. Overall mortality was significant (22%), and age and comorbidities such as heart failure and chronic kidney disease were found as indicators of poor prognosis, all of which were consistent with previous reports from Wuhan, China [50].
Data from retrospective studies from COVID-19 patients have provided some evidence to support that hypothesis [51][52][53][54][55]. Rothlin et al. conducted a pharmacological analysis that suggested telmisartan as the best candidate to study [56][57]. A multicenter clinical trial was conducted on 162 patients from 18 years of age hospitalized with COVID-19 (80 in the standard care and 78 in the telmisartan-added-to-standard care group) to assess whether 80 mg of telmisartan given twice daily would be effective in reducing lung inflammation and CRP levels at 5 and 8 days of treatment in COVID-19 hospitalized patients. For primary outcomes (5 and 9 days), the baseline absolute CRP serum levels were 5.53 ± 6.19 mg/dL and 9.04 ± 7.69 mg/dL in the standard care and telmisartan-added-to-standard care groups, respectively. On day 5, patients in the telmisartan-added-to-standard care group had a lower absolute CRP serum level than patients in the standard care group (standard care 6.06 ± 6.95 mg/dL; telmisartan-added-to-standard care 3.83 ± 5.08 mg/dL). Additionally, CRP serum levels were lower at day 8 in patients treated with telmisartan than those in the standard care group (control: 6.30 ± 8.19 mg/dL; telmisartan: 2.37 ± 3.47 mg/dL). Considering that baseline CRP was higher in the telmisartan arm, treatment with the AT1R antagonist resulted in an inversion of CRP at days 5 and 8. In this study, the differences observed in CRP plasma levels between telmisartan and control groups suggest an anti-inflammatory effect of ARB [58]. This effect may have been clinically relevant considering that patients with high CRP levels are more likely to have severe complications [58][59]. For secondary outcomes, patients who received telmisartan in addition to standard care had a median discharge time of 9 days, compared with 15 days in those who received only standard care [58]. However, no conclusive data from a prospective randomized trial on the use of ARBs on COVID-19 patients are available [56].
Interestingly, the PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of ARB valsartan, compared with placebo on the occurrence of ICU admission, mechanical ventilation, and death within 14 days of randomization in hospitalized SARS-CoV-2–infected patients (n = 651). This design trial will provide valuable insights into the use of ARB in SARS-CoV-2 infected patients and may contribute to improved treatment recommendations for a large group of patients in this time of the global COVID-19 pandemic [23].
It is also interesting to point out the action of other drugs rather than ARBs in inactivating the RAS signaling such as NSAIDs or bioactive proteins. In fact, Oh et al. have found that three NSAIDs (indomethacin, 6-methoxy-2-naphthylacetic acid, rofecoxib) showed high levels of binding affinity with RAS proteins, which could subsequently block RAS and its damaging effects induced by SARS-CoV-2 [60]. Additionally, bioactive proteins play critical functions in inhibiting the RAS signaling pathway. Some of them were isolated from the leaves of Morus alba and showed great potential in fostering anti-gout arthritis by blocking the RAS signaling pathway [61].

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Subjects: Microbiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Jean-Marc Sabatier
,
Ziad Fajloun
,
,
Julien Harb
,
Cedric Annweiler
,
Yingliang Wu
,
Zhijian Cao
,
Institut de Neurophysiopathologie
,
Ziad Abi Khattar
View Times: 488
Revisions: 2 times (View History)
Update Date: 12 Apr 2022
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