When Yanagisawa et al. 1 first identified endothelin (ET), a novel polypeptide vasoconstrictor for which numerous other functions were identified later,2 there was early widespread enthusiasm and great expectation for therapeutic opportunities. ET-1 is the most powerful vasoconstrictor in this peptide family; the ET system is complex with a converting enzyme and two receptors, ETA-R and ETB-R. The receptors offer an opportunity for selective blockade. ETA-R primarily mediates vasoconstriction and plays a role in the genesis of hypertension, states of endothelial dysfunction, insulin resistance, inflammation, and fibrosis. From a renal perspective, it is important to note that both ETA-R and ETB-R are found in the kidney, ETA-R in vessels and ETB-R mainly in the medulla3 but also in glomeruli.4 Of note, collecting duct ETB-R null mice develop elevated BP, pointing to a potential causal role in the genesis of hypertension.5 It was immediately perceived that such a multifunctional system might provide promising therapeutic targets, but early enthusiasm waned when renin-angiotensin system (RAS) blockade stole the show. But the slogan “they never come back” apparently is not true for drugs. Today it is clear that RAS blockade with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in renal patients does not consistently reduce proteinuria, which is not only a powerful predictor but also a promoter of renal progression; this is true for the dosages recommended for hypertension control and even for supramaximal dosages.6 This shortcoming has triggered a search for novel interventions in addition to RAS blockade, such as mineralocorticoid receptor blockade,7 renin inhibitors,8 and …
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