Endothelin receptors and their antagonists

Semin Nephrol. 2015 Mar;35(2):125-36. doi: 10.1016/j.semnephrol.2015.02.002.


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, ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ET(A) receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ET(B). The renal vascular endothelium only expresses the ET(B) subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ETB 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(B) in in the nephron to reduce salt and water re-absorption. In contrast, ET(A) 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(A) (BQ123, TAK-044) and ET(B) (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ET(A)/ET(B) antagonists or display ET(A) 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.

Keywords: Ambrisentan; antagonist; bosentan; endothelin-1; macitentan; sitaxentan.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Endothelin Receptor Antagonists / pharmacology*
  • Endothelium, Vascular / physiopathology*
  • Humans
  • Hypertension, Pulmonary* / drug therapy
  • Hypertension, Pulmonary* / metabolism
  • Hypertension, Pulmonary* / physiopathology
  • Receptors, Endothelin / metabolism*
  • Vasodilation / drug effects*


  • Endothelin Receptor Antagonists
  • Receptors, Endothelin