Endothelin receptors and their antagonists

Abstract

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.

Figure 1

Model of the ET-1 signaling pathway in the renal vasculature. The primary source of ET-1 production is the vascular endothelium, although it also is produced by other cell types in the kidney including epithelial cells. ET-1 is synthesized within the secretory vesicles of the constitutive pathway. Pro–ET-1 is processed to big ET-1 by the action of a furin convertase. Big ET-1 then is transformed to the mature, biologically active peptide ET-1, mainly through the action of ECE-1, although a second related enzyme, ECE-2, also may play a role, particularly under acidic pathophysiological conditions. ET-1 also is released from Weibel-Palade bodies of the regulated pathway in response to external stimuli. ET-1 released abluminally causes the underlying smooth muscle to contract, mainly via ET_A. The ligand-receptor complex then undergoes internalization to the endosome before recycling of the receptor to the cell surface. Some smooth muscle cells from specific vascular beds express a low density of ET_B, but ET_A antagonists are able to fully reverse an established ET-1 constrictor response, implying a minimal contribution. Binding to endothelial ET_B elicits an opposing vasodilatation via the release of relaxing factors as well as removal of ET-1 from the circulation by internalization to the lysosome and degradation.

Figure 2

Ratio of the density of human ET_A and ET_B measured using radioligand binding in the whole organ (brain, kidney, lung, liver, and heart) and measured in the medial smooth muscle layer of the vasculature within each organ. In human beings, kidney, lung, and liver are ET_B-rich, reflecting the expression of ET_B receptors on endothelium of the vasculature and other cell types such as the epithelium. In contrast, in the heart, ET_A are the principal subtype reflecting expression on myocytes. In the smooth muscle layer of all human vessels, ET_A are more abundant than ET_B.