Endothelin B receptor blockade accelerates disease progression in a murine model of autosomal dominant polycystic kidney disease.
J Am Soc Nephrol
; 18(2): 560-9, 2007 Feb.
Article
em En
| MEDLINE
| ID: mdl-17202412
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Rim Policístico Autossômico Dominante
/
Antagonistas do Receptor de Endotelina B
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Am Soc Nephrol
Assunto da revista:
NEFROLOGIA
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Reino Unido