Renal actions of endothelin: Linking cellular signaling pathways to kidney disease

Endothelin (ET), a potent endothelium-derived vasoconstrictor peptide [1] contributes to the regulation of glomerular function both through changes in hemodynamics and through changes in glomerular configuration. Three structurally and pharmacologically distinct isoforms of the peptide have been identified with a molecular weight of 2.5 kDa, each consisting of 21 amino acids. These isopeptides share a common structure with a hydrophobic C-terminal end and two disulfide bonds, thus forming a hairpin loop at the amino terminus. ET-1 differs from ET-2 by only two amino acids, and from ET-3 by six amino acids. Each ET isopeptide is encoded by separate genes at distinct chromosomal loci [2].All ETs are synthesized via proteolytical cleavage from specific prohormones (Fig. 1). Prepro ETs are long polypeptide chains consisting of ∼203 amino acids [1] which exhibit specific differences among the isopeptides. ET isopeptide precursors are proteolytically cleaved by processing endopeptidases that recognize paired basic amino acids (Arg-Arg or Lys-Arg) and thus form pro or big ET. Pro ET-1 is then converted to mature ET-1 by cleavage of the Trp21-Val22 bond via a highly specific endothelin-1-converting enzyme, which is a Phosphoramidon-sensitive, membrane bound metalloprotease (Fig. 1) [3–5]. Pro ET-3 is less susceptible to this protease, so that the presence of other types of endothelin-converting enzyme are suspected [5].ETs bind to two G-protein coupled receptors of ∼43 to ∼73 kD molecular weight [6–8], consisting of ∼415 to ∼427 amino acids and having seven transmembrane domains [6, 7]. The ETA receptor binds ET-1 with 2- to 10-fold higher affinity than ET-2 and > 100-fold higher affinity than ET-3 [6–9], whereas the ETB receptor has similar affinities to all three peptides [7, 8].Little is known about the fate of ET. ETs are either inactivated by receptor internalization or by enzymatic cleavage of the peptide prior to receptor coupling [10–13]