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1 Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
2 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
3 Department of Anesthesiology and Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN, USA
4 Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
5 Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: peter.aronson{at}yale.edu.
It has been proposed that ADPKD-affected renal epithelial cells undergo a phenotypic transition from a highly differentiated absorptive state to a much less differentiated secretory state during cystogenesis and that this transition is accompanied by loss of epithelial cell polarity and mistargeting of specific membrane proteins. We have conducted a detailed evaluation of this hypothesis in the Pkd2WS25/- mouse model of ADPKD. Ultrastructural analysis of Pkd2WS25/- cysts by electron microscopy confirmed that cystic epithelial cells progressively dedifferentiate with cyst enlargement. Immunocytochemical analysis of both early and late stage cysts with antibodies directed against the Na+/K+-ATPase, Ksp-cadherin, and E-cadherin failed to detect evidence of altered cyst cell polarity. The Na+/K+-ATPase and Ksp-cadherin were expressed exclusively on the basolateral membranes (BLM) of epithelial cells in all early cysts. Expression levels of both the Na+/K+-ATPase and Ksp-cadherin decreased progressively with the degree of cyst cell dedifferentiation, but neither protein was ever mislocalized. Highly dedifferentiated cysts did not express immunodetectable levels of either the Na+/K+-ATPase or Ksp-cadherin. E-cadherin was expressed prominently on the basolateral membranes of all cysts. Cysts were subsequently stained with an antibody directed against the secretory isoform of the Na+-K+-Cl- cotransporter NKCC1. NKCC1 expression was detected on the BLM of advanced cysts only. Our data are consistent with a model of progressive cystic epithelial cell dedifferentiation in which fluid accumulation in late stage cysts is mediated by transepithelial secretion of chloride rather than secretion of sodium by apical Na+/K+-ATPase.
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