Angiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases

Abstract

The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its downregulation, which subsequently leads to the dysregulation of the renin–angiotensin system (RAS) in favor of the ACE–angiotensin II (Ang II)–angiotensin II type I receptor (AT1R) axis. 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. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.

Vascular Implications of COVID-19: Role of Radiological Imaging, Artificial Intelligence, and Tissue Characterization: A Special Report

“…In addition to vasoconstriction and cytokine production, it causes several harmful effects on the vascular wall. This is largely due to its action on the angiotensin II type 1 (AT1) receptor [ 133 ]. Higher levels of endothelial Ang II trigger the production of reactive oxygen species (ROS) and result in the breakdown of nitric oxide (NO) production by reducing endothelial nitric oxide synthase (eNOS).…”

SARS-CoV-2, COVID-19, and Reproduction: Effects on Fertility, Pregnancy, and Neonatal Life

“…Neutrophil accumulation can lead to alveolar epithelial cell loss through its prooxidative role and the development of acute respiratory distress syndrome (ARDS) [ 67 ]. Therefore, pregnant women required extensive follow up and monitoring since severe infection and pulmonary deterioration lead to preterm birth in many reported cases [ 5 ]. That was the case of a COVID-19-positive pregnant woman, at 34 weeks, who developed severe ARDS after 4 days of fever and dyspnea.…”

“…The main symptoms of the SARS-CoV-2 infection disease include a dry cough, dyspnea, and fever. Fatigue, musculoskeletal discomfort, headaches, gastrointestinal problems, and a loss of smell and taste are also well-documented [ 4 , 5 , 6 ]. More studies are now investigating the effects of a SARS-CoV-2 infection on systems other than the respiratory system [ 7 ].…”

“…However, SARS-CoV-2 invasion and cellular internalization lead to the down-regulation of membrane-bound ACE2 and increase serum ACE2, which leads to Ang1-7 depletion and an unopposed AngII activity [ 9 ] ( Figure 1 A). Since the RAS is known to be of great importance in regulating different physiological processes (such as vasoconstriction, inflammation, angiogenesis, oxidative stress, and apoptosis) [ 5 ], the complications following the SARS-CoV-2 infection are likely due to RAS impairment [ 12 , 13 , 14 ]. ACE2 can be found at the surface of many cell types, including respiratory epithelial cells, cardiac fibroblasts, cardiomyocytes, endothelial cells, vascular smooth muscle cells (VSMCs), kidneys, gut, the central nervous system (CNS), and the reproductive system [ 15 ].…”

Protein nanoparticle-induced osmotic pressure gradients modify pulmonary edema through hyperpermeability in acute respiratory distress syndrome

“…A previous study suggested that the SARS-CoV2 spike protein on the viral envelope binds to its receptor, angiotensin-converting enzyme 2 (ACE2), causes downregulation of its activity on the target cell, which is involved in lung physiology and pathology through Renin–Angiotensin (RAS) and Kinin–Kallikrein (KKS) systems [ 6 ]. The downregulation of ACE2 activity decreases its ability to cleave angiotensin I (AngI) and angiotensin II (AngII) to Ang-(1–9) and Ang-(1–7), respectively, leading to an increased level of AngII and hyperactivation of the angiotensin II type 1 (AT1) receptor [ 7 , 8 ]. AngII–AT1R axis that regulates vasoconstrictive, proinflammatory, profibrotic, and prooxidative effects is a potential mechanism of cytokine storm and an acute respiratory distress syndrome (ARDS) [ 9 ].…”