Role of endothelin in the pathogenesis of acute renal failure

Shortly after the discovery of endothelin (ET) in 1988, ii was suggested that ET might be an important mediator of acute renal failure (ARF) because of its intense renal vasoconstrictive properties. Evidence has accumulated for supporting this hypothesis: Exogenous ET infused into the kidney is able to decrease renal blood flow and glomerular filtration rate to create conditions that can lead to ARF; ET also has glomerular and tubular effects; and ET mRNA expression, ET content and its affinity for ET receptors are elevated in ARF. In addition, since physiological and pathophysiological actions of ET in renal tissue are mediated by interaction with ETA and ETB receptor subtypes, a number of ET receptor antagonists have been developed and used to determine the pathophysiological role of ET peptide and ET receptor subtypes in the kidney. Many reports confirm beneficial effects of selective ETA and nonselective ETA/ETB receptor antagonists on renal dysfunction and degeneration in ARF. A recent study shows that renal dysfunction and histological damage observed in ischemic ARF are not improved by the treatment with a selective ETB receptor antagonist. Although the pathophysiological role of ETB-mediated ET action in the development of ARF is not fully understood, these observations strongly suggest that up-regulated endogenous ET contributes to the pathogenesis of ARF exclusively via ETA receptors and that compounds with ET, receptor antagonism are useful for the treatment of ARF. It is expected that such agents will have clinical applications in the future, and a number of drug candidates are now in development. (C) 2000 Prous Science. All rights reserved.