Regulation of Transepithelial Transport in PKD

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DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a common genetic human disease which is associated with a high morbidity and mortality. Autosomal dominant PKD (ADPKD) affects approximately 1: 1,000 people while autosomal recessive PKD (ARPKD) affects approximately 1: 20,000 five births. Approximately 50% of patients with ADPKD develop end-stage renal disease (ESRD) by the sixth decade of life while most infants with ARPKD that survive beyond the perinatal period develop chronic renal failure by early adolescence. In PKD cyst growth and expansion destroys normal renal parenchyma and leads to renal failure. In ADPKD, cysts, which can arise from any tubular segment, "bud" off from the nephron and no longer communicate with the tubule from which they originate. In contrast, cysts in ARPKD are actually ectatic dilated collecting ducts which remain contiguous with the remaining nephron, allowing for urine to continue to flow through the dilated collecting system. Evidence from experimental ADPKD models and human disease suggests that cyst formation and expansion arise, at least in part, from transepithelial solute and fluid secretion. In contrast to the latter observation we have recently reported that ARPKD cyst lining epithelium, at least early in disease, is a Na absorptive epithelium. The rate limiting step in transepithelial Na absorption lies at the level of the apical epithelial Na channel (ENaC) and the steady state levels of the alpha and beta subunits of this channel are highly expressed in ARPKD cells. Based on these results we hypothesize that ARPKD is associated with upregulated Na absorption, presumably mediated by ENaC, which we speculate contributes to the early onset of hypertension. This hypothesis will be explored by answering the following specific aims and using a combination of molecular, electrophysiologic, and functional techniques: SAI: To identify the mechanism or pathway for Na absorption in ARPKD cystic epithelium. SA II: To identify those factors that regulate the avid Na absorption seen in ARPKD cyst lining epithelial cells.