Genetic Manipulation of the Endothelin System

Abstract

The endothelin (ET) system consists of the three 21-amino acid isopeptides, ET-1, ET-2, and ET-3 synthesized primarily by a family of unique endothelin converting enzymes (ECE). These peptides exert a wide variety of physiological and pathophysiological effects by activating a pair of classical G-protein coupled receptors, ETA and ETB. Genetic manipulation of the ET system in rodents has revealed an important role of this system on fetal organ development, blood pressure regulation, and end-organ damage, especially in lung and kidney. Overexpression of ET-1 in mice demonstrates hypertrophic, fibrotic, and inflammatory effects on vasculature, heart, lung and kidney tissues, while overexpression of human ET-2 in rats shows a primary fibrotic effect in glomeruli. Studies from systemic knockout models of the ET system are uniformly lethal, but reveal that the ET-1/ECE-1/ETA-mediated signaling pathway is necessary for facial and cardiovascular formation, while ET-3/ECE-1/ETB signaling pathway is important for creation of neural crest-derived enteric neurons and epidermal melanocytes during embryonic development. Furthermore, cell-specific deletion of the ET system in the renal collecting duct leads to impaired water and sodium excretion, increased epithelial sodium channel activity and hypertension. In summary, it is clear that genetic manipulation of the ET system has been, and will continue to be, a powerful tool to aid our understanding of physiological and pathological actions of this complex autocrine and paracrine system.