Histopathological analysis of renal cystic epithelia in the Pkd2WS25/- mouse model of ADPKD.
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.
Thomson
R Brent
RB
Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8029, USA.
Mentone
SueAnn
S
Kim
Robert
R
Earle
Karen
K
Delpire
Eric
E
Somlo
Stefan
S
Aronson
Peter S
PS
D000483:Alleles; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D004195:Disease Models, Animal; D004848:Epithelium / Q000473:pathology; D020868:Gene Silencing; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000235:genetics*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D014018:Tissue Distribution
D015820:Cadherins; C491946:Cdh16 protein, mouse; D000091283:Protein Kinase D2; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D011494:Protein Kinases; D000254:Sodium-Potassium-Exchanging ATPase