Histopathological analysis of renal cystic epithelia in the Pkd2WS25/- mouse model of ADPKD

Am J Physiol Renal Physiol. 2003 Nov;285(5):F870-80. doi: 10.1152/ajprenal.00153.2003. Epub 2003 Jul 8.

Abstract

It has been proposed that autosomal dominant polycystic kidney disease (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 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 Na+-K+-ATPase, Ksp-cadherin, and E-cadherin failed to detect evidence of altered cyst cell polarity. 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 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 Na+-K+-ATPase or Ksp-cadherin. E-cadherin was expressed prominently on the BLM 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles*
  • Animals
  • Cadherins / metabolism
  • Disease Models, Animal
  • Epithelium / pathology
  • Gene Silencing*
  • Immunohistochemistry
  • Kidney / metabolism
  • Kidney / pathology*
  • Mice
  • Microscopy, Electron
  • Microscopy, Electron, Scanning
  • Polycystic Kidney, Autosomal Dominant / genetics*
  • Polycystic Kidney, Autosomal Dominant / metabolism
  • Polycystic Kidney, Autosomal Dominant / pathology*
  • Protein Kinases / genetics*
  • Sodium-Potassium-Chloride Symporters / metabolism
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Solute Carrier Family 12, Member 2
  • Tissue Distribution

Substances

  • Cadherins
  • Cdh16 protein, mouse
  • Slc12a2 protein, mouse
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 2
  • Protein Kinases
  • protein kinase D2
  • Sodium-Potassium-Exchanging ATPase