Endothelin Receptors and Their Antagonists

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All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to two G-protein-coupled receptors, ET<inf>A</inf> and ET<inf>B</inf>, whereas at physiological concentrations ET-3 has little affinity for the ET<inf>A</inf> receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ET<inf>B</inf>. The renal vascular endothelium only expresses the ET<inf>B</inf> subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ET<inf>B</inf> in kidney, as well as liver and lungs, also has a critical role in scavenging ET-1 from the plasma. The third major function is ET-1 activation of ET<inf>B</inf> in in the nephron to reduce salt and water re-absorption. In contrast, ET<inf>A</inf> predominate on smooth muscle, causing vasoconstriction and mediating many of the pathophysiological actions of ET-1. The role of the two receptors has been delineated using highly selective ET<inf>A</inf> (BQ123, TAK-044) and ET<inf>B</inf> (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ET<inf>A</inf>/ET<inf>B</inf> antagonists or display ET<inf>A</inf> selectivity, have been approved for clinical use but to date are limited to pulmonary hypertension. Ambrisentan is in clinical trials in patients with type 2 diabetic nephropathy. This review summarizes ET-receptor antagonism in the human kidney, and considers the relative merits of selective versus nonselective antagonism in renal disease.




Maguire, J. J., & Davenport, A. P. (2015, March 1). Endothelin Receptors and Their Antagonists. Seminars in Nephrology. W.B. Saunders. https://doi.org/10.1016/j.semnephrol.2015.02.002

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