Endothelin in polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease in man and is caused by germline mutations in PKD1 or PKD2. Affected patients develop progressively enlarged kidneys due to the growth of multiple renal epithelial cysts. Several studies have demonstrated marked intrafamilial phenotypic variability in PKD1 or PKD2 pedigrees, indicating the importance of nonallelic factors such as genetic modifying loci in determining individual phenotype. Endothelin (ET)-1 exerts multiple and often opposing effects on different aspects of renal physiology through its major ET receptor subtypes, ET(A) and ET(B). Recent studies have reported that EDN1 and EDNRA polymorphisms can influence the age of onset of end-stage renal disease in ADPKD. Both circulating and local ET-1 systems are abnormally activated in human disease and experimental models, and ET(A) receptor expression is specifically upregulated in human ADPKD kidneys. Overexpression of ET-1 in transgenic mice is sufficient to trigger cyst initiation. However, studies utilizing selective ET(A) and ET(B) receptor antagonists to delay cystic disease progression in rodent PKD models have proved disappointing and do not support further extension into clinical trials. A critical balance between ET(A) and ET(B) action in the cystic kidney appears to be necessary to maintain kidney structure and function. Current evidence suggests that ET-1 and its receptors act as major modifying genes for renal disease progression in ADPKD. The future challenge will be to translate these findings to modify disease severity or for predicting prognosis in man.