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.
- Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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