Pathophysiology of ARPKD: role of aberrant transport

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The hereditary forms of polycystic kidney disease (PKD) include the common autosomal dominant form (ADPKD), affecting 1 in approximately 1000 of the population, and the less common autosomal recessive form (ARPKD), affecting 1 in approximately 20,000 live births. Both diseases are characterized by the formation and expansion of cysts derived from specific segments of the nephron. In ADPKD, the gradual destruction of normal renal parenchyma by cysts arising in multiple nephron segments lead to renal failure in approximately 50% of patients by the sixth decade of life. ARPKD, a disease with high infant morbidity, is characterized by the progressive dilatation of collecting ducts, the nephron segment responsible for the final renal regulation of Na, K, acid-base and water balance. Three mechanisms have been implicated in the process of cyst formation and expansion: cell proliferation, abnormal extracellular matrix and adhesion, and net transepithelial fluid. Whereas data exists to implicate the former two processes in the pathogenesis of ARPKD, little is known about the regulation of transepithelial solute and water transport in this disease. Our long term goal is to identify alterations in the expression and regulation of epithelial cell transport pathways that contribute not only to cyst expansion, but also the early onset of hypertension and polyuria in APRKD. The hypotheses we propose to examine in this 5-year application are focused on (I) characterizing the molecular and functional expression of ion channels, transporters, and receptors, and (II, III) exploring the mechanisms by which aberrant autocrine/paracrine signaling and/or cellular responses to biomechanical forces lead to dysregulated transepithelial transport in ARPKD collecting dust cysts. To best understand the pathogenesis of human disease, we propose to perform most studies described in this application in immortalized principal cell lines derived from human ARPKD collecting duct cysts or age-matched normal human kidney (NHK). Parallel studies will also be performed in the orpk murine model of ARPKD, whose microdissected tubules can be isolated and microperfused in vitro.