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Cited by 541Renin-Angiotensin System StudiesCardiovascular, Neuropeptides, and Oxidative Stress ResearchReceptor Mechanisms and Signaling

Pleiotropic AT1 Receptor Signaling Pathways Mediating Physiological and Pathogenic Actions of Angiotensin II

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Hunyady, László, Catt, Kevin J.·2006·Molecular Endocrinology
DOI 10.1210/me.2004-0536
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Abstract

Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT1 receptor (AT1R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT1R activation via Gq/11 stimulates phospholipases A2, C, and D, and activates inositol trisphosphate/Ca2+ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-kappaB pathway. The AT1R also signals via Gi/o and G11/12 and stimulates G protein-independent signaling pathways, such as beta-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT1R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT1R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT1R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT1R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II's pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT1R antagonists, in addition to their established therapeutic actions in essential hypertension.

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  • The AngII-AT1R axis activates the NF-κB pathway through various growth factors and pro-inflammatory cytokines.

    “The AngII–AT1R axis activates the NF-κB pathway through various growth factors and pro-inflammatory cytokines (347, 348).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [348]

    The Ang II-Stimulated ROS Generation section reports that Ang II–AT1R signaling stimulates NF-κB activity in human neutrophils. It does not establish that growth factors or pro-inflammatory cytokines mediate that activation; it says the mechanisms of cytokine effects require further study. The Jak/STAT section discusses cytokine-mediated signaling, but for Jak/STAT rather than NF-κB. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Octreotide can reduce orthostatic tachycardia in POTS patients to a similar extent as midodrine, but it lacks a widely available oral dosage form and must be administered subcutaneously.

    “While it can reduce orthostatic tachycardia in POTS patients to a similar extent as midodrine, it lacks a widely available oral dosage form and must be administered subcutaneously (60, 61).”

    From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [60]

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Authors
Hunyady, L., & Catt, K. J.
Affiliations
  • Department of Physiology (L.H.), Faculty of Medicine, Semmelweis University, H-1444 Budapest, Hungary;
  • National Institutes of Health (US)
Corresponding author
Catt, Kevin J.
Venue
Molecular Endocrinology
Publisher
The Endocrine Society
Published
2006-05-01
Volume
20
Issue
5
Pages
953-970
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
DOI
10.1210/me.2004-0536
OpenAlex
W2031150814
Cited by
541
References
208
Citations by year
2026: 10 · 2025: 5 · 2024: 12 · 2023: 16 · 2022: 24 · 2021: 29 · 2020: 26 · 2019: 20 · 2018: 27 · 2017: 24 · 2016: 29 · 2015: 30 · 2014: 32 · 2013: 36 · 2012: 43
FWCI
4.18
Type
journal article
Language
en
Open access
Locations
  • Molecular Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust (069416)
  • Hungarian Scientific Research Fund
  • Hungarian Science Foundation
  • National Institutes of Health
  • National Institute of Child Health and Human Development
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
angiotensin II, angiotensin II type 1 receptor, Gq/11 signaling, Gi/o signaling, beta-arrestin, MAPK signaling, JAK/STAT signaling, receptor tyrosine kinase, NF-κB, reactive oxygen species, aldosterone, blood pressure regulation, cardiovascular disease, kidney disease, metabolic disorders, tumor progression, metastasis, ACE inhibitors, AT1 receptor antagonists, essential hypertension
MeSH terms
Angiotensin II, Animals, Cardiovascular Diseases, Diabetes Mellitus, Humans, Neoplasms, Signal Transduction, Receptor, Angiotensin, Type 1

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