Ion Transport Dysregulation in Cilium-deficient ARPKD

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DESCRIPTION (provided by applicant): Both genetic forms of polycystic kidney disease (PKD) present in human or mouse models as a profound change in renal tubule or epithelial cell morphology and architecture due to mutations in proteins that localize, at least in part, to the apical central monocilium of the cortical collecting duct (CCD) principal cell (PC cell). Once the genetic and biochemical consequences of PKD are manifested in this change in morphology, the change in cellular or tubular architecture affects transepithelial ion transport profoundly. In human autosomal recessive PKD (ARPKD) monolayers, there is evidence of sodium hyperabsorption, although the sodium transport mechanisms are not yet clearly defined. This abnormality may explain early onset hypertension observed in the majority of human ARPKD patients. Using mouse renal epithelial cells that are immortalized due to genetic cross with the Immortomouse and form polarized epithelial cell monolayers from wild-type, mutant, and genetically rescued PC cells from the Oak Ridge polycystic kidney (orpk) mouse CCD of very high electrical resistance, our laboratory has gathered preliminary data showing upregulated absorptive sodium transport in mouse orpk ARPKD mutant cortical collecting duct (CCD) principal epithelial cells (PC cells) grown as polarized monolayers and lacking apical central monocilia versus control cilium-competent PC cell monolayers. These upregulated sodium currents may represent ENaC- and NHE-mediated sodium hyperabsorption. Taken together, the literature, the experience of our collaborative research group, our current preliminary work, and the constructive criticism of the reviewers of our original application led us to formulate the following working hypothesis: CCDs from mouse models of ARPKD that lack apical central monocilia have upregulated ENaC- and NHE-mediated sodium absorption and resultant hypertension. Interrelated specific aims derive from this hypothesis and are designed to understand the cellular and molecular mechanisms that underlie this ARPKD disease phenotype.