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Review ArticleReview Article

The Angiotensin AT2 Receptor: From a Binding Site to a Novel Therapeutic Target

U. Muscha Steckelings, Robert E. Widdop, Edward D. Sturrock, Lizelle Lubbe, Tahir Hussain, Elena Kaschina, Thomas Unger, Anders Hallberg, Robert M. Carey and Colin Sumners
Rhian Touyz, ASSOCIATE EDITOR
Pharmacological Reviews October 2022, 74 (4) 1051-1135; DOI: https://doi.org/10.1124/pharmrev.120.000281
U. Muscha Steckelings
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Robert E. Widdop
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Edward D. Sturrock
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Lizelle Lubbe
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Tahir Hussain
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Elena Kaschina
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Thomas Unger
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Anders Hallberg
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Robert M. Carey
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Colin Sumners
Institute of Molecular Medicine, Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark (U.M.S.); Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.E.W.); Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa (E.D.S., L.L.); Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas (T.H.); Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular–Metabolic–Renal (CMR) Research Center, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (E.K.); CARIM – School for Cardiovascular Diseases, Maastricht University, The Netherlands (T.U.); Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden (A.H.); Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia (R.M.C.); and Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida (C.S.)
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Rhian Touyz
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Abstract

Discovered more than 30 years ago, the angiotensin AT2 receptor (AT2R) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The AT2R represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the AT2R, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the AT2R, including its structure, intracellular signaling, homo- and heterodimerization, and expression. AT2R-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the AT2R and its abundant protective effects in multiple experimental disease models and expound on AT2R ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for AT2R research.

Significance Statement The angiotensin AT2 receptor (AT2R) is now regarded as a fully functional and important component of the renin-angiotensin system, with the potential of exerting protective actions in a variety of diseases. This review provides an in-depth view of the AT2R, which has progressed from being an enigma to becoming a therapeutic target.

Footnotes

    • Received December 23, 2020.
    • Revision received May 19, 2022.
    • Accepted June 27, 2022.
  • This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL136595] (to C.S.) and [Grant 2-R01-HL128189] (to R.M.C.), by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK061578] (to T.H.) and [Grant R01-DK117495] (to T.H.), by a UK Global Challenge Research Fund grant from Synchrotron Techniques for African Research and Technology (START) [Science and Technology Facilities Council Grant ST/R002754/1] (to L.L.), by the Independent Research Fund Denmark [Grant 0134-00297B] (to U.M.S.), and by the Novo Nordisk Foundation [Grant NNF19OC0058592] (to U.M.S.).

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • dx.doi.org/10.1124/pharmrev.120.000281.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 74 (4)
Pharmacological Reviews
Vol. 74, Issue 4
1 Oct 2022
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Review ArticleReview Article

Angiotensin AT2 Receptor: A Novel Therapeutic Target

U. Muscha Steckelings, Robert E. Widdop, Edward D. Sturrock, Lizelle Lubbe, Tahir Hussain, Elena Kaschina, Thomas Unger, Anders Hallberg, Robert M. Carey and Colin Sumners
Pharmacological Reviews October 1, 2022, 74 (4) 1051-1135; DOI: https://doi.org/10.1124/pharmrev.120.000281

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Review ArticleReview Article

Angiotensin AT2 Receptor: A Novel Therapeutic Target

U. Muscha Steckelings, Robert E. Widdop, Edward D. Sturrock, Lizelle Lubbe, Tahir Hussain, Elena Kaschina, Thomas Unger, Anders Hallberg, Robert M. Carey and Colin Sumners
Pharmacological Reviews October 1, 2022, 74 (4) 1051-1135; DOI: https://doi.org/10.1124/pharmrev.120.000281
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  • Article
    • Visual Overview
    • Abstract
    • I. Introduction
    • II. The Classic and the Protective Renin-Angiotensin System
    • III. The Angiotensin AT2-Receptor
    • IV. AT2-Receptor Selective Ligands
    • V. AT2-Receptor Physiology
    • VI. AT2-Receptor in Disease
    • VII. AT2-Receptor Agonists and Antagonists in Drug Development Programs
    • VIII. Open Questions in AT2R Research
    • IX. Conclusions and Future Perspectives
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