Impaired epithelial Na(+) channels activity contributes to cystogenesis and development of autosomal recessive polycystic kidney disease in PCK rats

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder characterized by the development of renal cysts of the tubular epithelial cell origin. Epithelial Na(+) channel (ENaC) is responsible for sodium reabsorption in the aldosterone-sensitive distal nephron. Here we investigated the ENaC expression and activity in cystic tissue taken from rats with ARPKD. METHODS: PCK rats were treated with the selective ENaC inhibitor benzamil given in the drinking water, and after 4 or 12 weeks the severity of morphological malformations in the kidneys was assessed. ENaC and AQP2 expression and ENaC activity were tested with immunohistochemistry and patch clamp electrophysiology, respectively. RESULTS: Treatment with benzamil exacerbated development of cysts compared to the vehicle-treated animals. In contrast, the 12 weeks treatment with a loop diuretic furosemide had no effect on cystogenesis. Single channel patch clamp analysis revealed that ENaC activity in the freshly isolated cystic epithelium was significantly lower than in the non-cystic collecting ducts isolated from PCK or normal Sprague-Dawley rats. Immunohistochemical analysis confirmed that β-ENaC and AQP2 expressions in cysts are decreased compared to non-dilated tubules from PCK rat kidneys. CONCLUSION: We demonstrated that cystic epithelium exhibits low ENaC activity and this phenomenon can contribute to cyst progression.