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From the Department of Medicine,*
Mount Sinai School of
Medicine, New York, New York; the Division of
Cardiology,
University of Maryland School of
Medicine, Baltimore, Maryland; and the Department of
Biology,
The Johns Hopkins University,
Baltimore, Maryland
Autosomal dominant polycystic kidney disease (ADPKD) is a
common genetic disease of the kidney, characterized by cystic
enlargement of renal tubules, aberrant epithelial
proliferation, and ion and fluid secretion into the lumen.
Previous studies have shown abnormalities in polarization of membrane
proteins, including mislocalization of the NaK-ATPase to the
apical plasma membranes of cystic epithelia. Apically located
NaK-ATPase has previously been shown to be fully functional in
vivo and in membrane-grown ADPKD epithelial cells in
vitro, where basal-to-apical 22Na transport
was inhibited by application of ouabain to the apical membrane
compartment. Studies were conducted with polymerase chain
reaction-generated specific riboprobes and polyclonal peptide
antibodies against human sequences of 
1, 3,
ß1, and ß2 subunits of NaK-ATPase. High levels of
expression of 1 and ß1 messenger RNA were detected in ADPKD and
age-matched normal adult kidneys in vivo, whereas
ß2 messenger RNA was detected only in ADPKD kidneys. Western blot
analysis and immunocytochemical studies showed that, in normal
adult kidneys, peptide subunit-specific antibodies against 1
and ß1 localized to the basolateral membranes of normal renal
tubules, predominantly thick ascending limbs of Henle’s loop.
In ADPKD kidneys, 1 and ß2 subunits were localized to the
apical epithelial cell membranes, whereas ß1 was distributed
throughout the cytoplasm and predominantly in the endoplasmic
reticulum, but was not seen associated with cystic epithelial
cell membranes or in cell membrane fractions. Polarizing,
renal-derived epithelial Madin Darby canine kidney cells,
stably expressing normal or N-terminally truncated chicken ß1
subunits, showed selective accumulation in the basolateral
Madin Darby canine kidney cell surface, whereas
c-myc epitope-tagged chicken ß2 or human ß2
subunits accumulated selectively in the apical cell surface.
Similarly, human ADPKD epithelial cell lines, which
endogenously expressed 1 and ß2 NaK-ATPase subunits,
showed colocalization at the apical cell surface and coassociation by
immunoprecipitation analysis. These results are consistent with a model
in which the additional transcription and translation of the ß2
subunit of NaK-ATPase may result in the apical mislocalization of
NaK-ATPase in ADPKD cystic epithelia.
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