The Angiotensin AT2 Receptor

Unger, Thomas; Steckelings, Ulrike Muscha; Dzau, Victor J.

doi:10.1016/b978-0-12-801364-9.00001-8

Cited by 26 publications

(46 citation statements)

References 91 publications

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“…In addition, ACE2 expression is known to be homeostatically regulated through many intra- and extra-cellular pathways which are not well understood. 45 , 46 , 74 , 125 , 130 , 184 , 203 , 231 Correctly interpreting responses of dynamically regulated systems to perturbations is complicated by the presence of regulation, and usually requires a model-based approach. 44 Animal models that can be infected by SARS-CoV-2 and show similar dysregulation in the RAS would be excellent tools to study the connection between these two factors.…”

Section: Ace2/ras Connecting Vascular/bp To Gut and Renalmentioning

confidence: 99%

Significant Unresolved Questions and Opportunities for Bioengineering in Understanding and Treating COVID-19 Disease Progression

et al. 2020

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COVID-19 is a disease that manifests itself in a multitude of ways across a wide range of tissues. Many factors are involved, and though impressive strides have been made in studying this novel disease in a very short time, there is still a great deal that is unknown about how the virus functions. Clinical data has been crucial for providing information on COVID-19 progression and determining risk factors. However, the mechanisms leading to the multi-tissue pathology are yet to be fully established. Although insights from SARS-CoV-1 and MERS-CoV have been valuable, it is clear that SARS-CoV-2 is different and merits its own extensive studies. In this review, we highlight unresolved questions surrounding this virus including the temporal immune dynamics, infection of non-pulmonary tissue, early life exposure, and the role of circadian rhythms. Risk factors such as sex and exposure to pollutants are also explored followed by a discussion of ways in which bioengineering approaches can be employed to help understand COVID-19. The use of sophisticated in vitro models can be employed to interrogate intercellular interactions and also to tease apart effects of the virus itself from the resulting immune response. Additionally, spatiotemporal information can be gleaned from these models to learn more about the dynamics of the virus and COVID-19 progression. Application of advanced tissue and organ system models into COVID-19 research can result in more nuanced insight into the mechanisms underlying this condition and elucidate strategies to combat its effects.

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Section: Ace2/ras Connecting Vascular/bp To Gut and Renalmentioning

confidence: 99%

Significant Unresolved Questions and Opportunities for Bioengineering in Understanding and Treating COVID-19 Disease Progression

et al. 2020

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“…However, in the late 1980s the first evidence of a second protein binding AngII appeared in the literature, the angiotensin II type 2 receptor (AT 2 R) ,. This receptor proved to be an enigmatic protein, which in recent years has emerged as a promising new drug target …”

Section: Introductionmentioning

confidence: 99%

A Series of Analogues to the AT₂R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode

et al. 2019

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We here report on our continued studies of ligands binding to the promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five‐fold improved affinity to AT2R as compared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.

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“…Recent publications highlight ACE2 as a cell-entry receptor for SARS-CoV and SARS-CoV-2. Less attention is given to other, in particular protective, components of the Renin Angiotensin System (RAS) (Unger et al 2015 ). RAS has a double nature, like the two-faced ancient Roman god Janus, which simultaneously looks in opposite directions.…”

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confidence: 99%

“…ARBs block the AT 1 R and thus Ang II can activate the unopposed protective receptor AT 2 R and further, after ACE2-mediated conversion of Ang II into Ang-(1–7), also the MasR. Unfortunately, ARBs exert only limited therapeutic effect in tissue injury (Unger et al 2015 ). Moreover, ARBs may reduce blood pressure, which in case of critically ill patients may lead to unwanted hypotension.…”

mentioning

confidence: 99%

“…AT 2 R / MasR: angiotensin II type 2 receptor or Mas receptor or AT 2 R-MasR heterodimers; TGFBR2: transforming growth factor beta receptor II; AT 1 R: angiotensin II type 1 receptor; RTKs: receptor tyrosine kinases; Akt: protein kinase B; PTP: protein tyrosine phosphatase; PSP: protein serine/threonine phosphatase; eNOS: nitric oxide synthase 3; NO: nitric oxide; cGMP: cyclic guanosine monophosphate; MMP9: matrix metallopeptidase 9; TGFβ: transforming growth factor beta; PDGF: platelet-derived growth factor; FGF: fibroblast growth factor; CTGF: connective tissue growth factor; VEGF: vascular endothelial growth factor; ECM: extracellular matrix; ERK: extracellular signal-regulated kinases; MAPK: mitogen-activated protein kinase; NOX: NADPH oxidase; ROS: reactive oxygen species; NFκB: nuclear factor kappa B; Gαi: G protein alpha i subunit; ATIP: AT 2 R-interacting proteins/microtubule-associated scaffold proteins; PP2A: protein phosphatase 2A; SHP-1: Src homology region 2 domain-containing phosphatase-1; MKP-1: MAPK Phosphatase 1. The pathways are based on: Unger et al 2015 ; Sumners et al 2019 ; Zhang et al 2014 ; Leonhardt et al 2017 ; Chappell and Al Zayadneh 2017 …”

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confidence: 99%

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Does activation of the protective Renin-Angiotensin System have therapeutic potential in COVID-19?

Namsolleck¹,

Moll

2020

Mol Med

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Infection of lung cells by the corona virus results in a loss of the balance between, on the one hand, angiotensin IImediated stimulation of the angiotensin II type 1 receptor and, on the other hand, stimulation of the angiotensin II type 2 receptor and/or the Mas receptor. The unbalanced enhanced stimulation of the angiotensin II type 1 receptor causes inflammation, edema and contributes to the pathogenesis of severe acute respiratory distress syndrome. Here we hypothesize that stable, receptor-specific agonists of the angiotensin II type 2 receptor and of the Mas receptor are molecular medicines to treat COVID-19 patients. These agonists have therapeutic potential in the acute disease but in addition may reduce COVID-19-associated long-term pulmonary dysfunction and overall end-organ damage of this disease.

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The Angiotensin AT2 Receptor

Cited by 26 publications

References 91 publications

Significant Unresolved Questions and Opportunities for Bioengineering in Understanding and Treating COVID-19 Disease Progression

Significant Unresolved Questions and Opportunities for Bioengineering in Understanding and Treating COVID-19 Disease Progression

A Series of Analogues to the AT₂R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode

Does activation of the protective Renin-Angiotensin System have therapeutic potential in COVID-19?

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The Angiotensin AT2 Receptor

Cited by 26 publications

References 91 publications

Significant Unresolved Questions and Opportunities for Bioengineering in Understanding and Treating COVID-19 Disease Progression

Significant Unresolved Questions and Opportunities for Bioengineering in Understanding and Treating COVID-19 Disease Progression

A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode

Does activation of the protective Renin-Angiotensin System have therapeutic potential in COVID-19?

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A Series of Analogues to the AT₂R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode