title: Endothelin B receptor blockade accelerates disease progression in a murine model of autosomal dominant polycystic kidney disease.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease that causes kidney failure and accounts for 10% of all patients who are on renal replacement therapy. However, the marked phenotypic variation between patients who carry the same PKD1 or PKD2 mutation suggests that nonallelic factors may have a greater influence on the cystic phenotype. Endothelin-1 (ET-1) transgenic mice have been reported to develop profound renal cystic disease and interstitial fibrosis without hypertension. The hypothesis that ET-1 acts as a modifying factor for cystic disease progression was tested in an orthologous mouse model of ADPKD (Pkd2(WS25/-)). Four experimental groups (n = 8 to 11) were treated from 5 to 16 wk of age with the highly selective orally active receptor antagonists ABT-627 (ETA) and A-192621 (ETB) singly or in combination. Unexpected, ETB blockade led to accelerated cystic kidney disease. Of significance, this was associated with a reduction in urine volume and sodium excretion and increases in urine osmolarity and renal cAMP and ET-1 concentrations. The deleterious effect of chronic ETB blockade was neutralized by simultaneous ETA blockade. ETA blockade alone resulted in a significant increase in tubular cell proliferation but did not alter the cystic phenotype. It is concluded that the balance between ETA and ETB signaling is critical for maintaining tubular structure and function in the cystic kidney. These results implicate ET, acting via vasopressin-dependent and independent pathways, as a major modifying factor for cystic disease progression in human ADPKD.
authors.affiliation: Academic Nephrology Unit, The Henry Wellcome Laboratories for Medical Research, School of Medicine and Biomedical Sciences, University of Sheffield, Beech Hill Road. Sheffield, United Kingdom.
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Chang
authors.forename: Emma
authors.initials: E
authors.lastname: Parker
authors.forename: Meguid
authors.initials: M
authors.lastname: El Nahas
authors.forename: John L
authors.initials: JL
authors.lastname: Haylor
authors.forename: Albert C M
authors.initials: AC
authors.lastname: Ong
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018450:Disease Progression; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D005355:Fibrosis; D006801:Humans; D051379:Mice; D016891:Polycystic Kidney, Autosomal Dominant / Q000473:pathology* / Q000503:physiopathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6