Renal tubule Na,K-ATPase polarity in glucocorticoid-induced polycystic kidney disease.

Ogborn, Malcolm R.; Sareen, Sanjay; Grimm, Paul

doi:10.1177/41.4.8383715

Cited by 14 publications

(8 citation statements)

References 13 publications

(6 reference statements)

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“…Our previous results, as well as those in this report, show that specific membrane proteins are missorted and targeted to inappropriate membranes in ADPKD, leading to mispolarization of epithelia with pathophysiological consequences for proliferation and ion and fluid secretion. Apical mispolarization of NaK-ATPase has also been confirmed by other laboratories, in human autosomal recessive polycystic kidney disease 50 ; several genetic models of autosomal recessive polycystic kidney disease, including the cpk, pcy, and other genetic models of polycystic kidney disease and glucocorticoid-induced polycystic kidney disease in mice, [51][52][53] as well as in zebrafish pronephric cystic mutants. 54 Of great interest for the putative role of polycystin-1 in focal adhesion multiprotein complexes, tension knockout mice also show Figure 8.…”

Section: Discussionsupporting

confidence: 54%

Apical Plasma Membrane Mispolarization of NaK-ATPase in Polycystic Kidney Disease Epithelia Is Associated with Aberrant Expression of the β2 Isoform

Wilson

Devuyst

et al. 2000

The American Journal of Pathology

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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 (22)Na 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 alpha1, alpha3, beta1, and beta2 subunits of NaK-ATPase. High levels of expression of alpha1 and beta1 messenger RNA were detected in ADPKD and age-matched normal adult kidneys in vivo, whereas beta2 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 alpha1 and beta1 localized to the basolateral membranes of normal renal tubules, predominantly thick ascending limbs of Henle's loop. In ADPKD kidneys, alpha1 and beta2 subunits were localized to the apical epithelial cell membranes, whereas beta1 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 beta1 subunits, showed selective accumulation in the basolateral Madin Darby canine kidney cell surface, whereas c-myc epitope-tagged chicken beta2 or human beta2 subunits accumulated selectively in the apical cell surface. Similarly, human ADPKD epithelial cell lines, which endogenously expressed alpha1 and beta2 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 beta2 subunit of NaK-ATPase may result in the apical mislocalization of NaK-ATPase in ADPKD cystic epithelia.

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Section: Discussionsupporting

confidence: 54%

Apical Plasma Membrane Mispolarization of NaK-ATPase in Polycystic Kidney Disease Epithelia Is Associated with Aberrant Expression of the β2 Isoform

Wilson

Devuyst

et al. 2000

The American Journal of Pathology

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“…Several of the animal models of polycystic kidney ble that separate cell populations are responsible for the ability of the monolayers to both absorb and secrete fluid. disease have also been examined for mislocation of Na / -K / -ATPase (4,9,26,97,127,129,146,161). None of the That possibility is diminished in the microcysts that were grown by seeding a small number of cells within a colla-studies found the enzyme to be exclusively located in the apical membrane.…”

Section: B Autosomal Dominant Polycystic Kidney Disease Tissuementioning

confidence: 99%

Epithelial Transport in Polycystic Kidney Disease

Sullivan

Wallace

Grantham

1998

Physiological Reviews

183

168

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In autosomal dominant polycystic kidney disease (ADPKD), the genetic defect results in the slow growth of a multitude of epithelial cysts within the renal parenchyma. Cysts originate within the glomeruli and all tubular structures, and their growth is the result of proliferation of incompletely differentiated epithelial cells and the accumulation of fluid within the cysts. The majority of cysts disconnect from tubular structures as they grow but still accumulate fluid within the lumen. The fluid accumulation is the result of secretion of fluid driven by active transepithelial Cl- secretion. Proliferation of the cells and fluid secretion are activated by agonists of the cAMP signaling pathway. The transport mechanisms involved include the cystic fibrosis transmembrane conductance regulator (CFTR) present in the apical membrane of the cystic cells and a bumetanide-sensitive transporter located in the basolateral membrane. A lipid factor, called cyst activating factor, has been found in the cystic fluid. Cyst activating factor stimulates cAMP production, proliferation, and fluid secretion by cultured renal epithelial cells and also is a chemotactic agent. Cysts also appear in the intrahepatic biliary tree in ADPKD. Normal ductal cells secrete Cl- and HCO3-. The cystic ductal cell also secretes Cl-, but HCO3- secretion is diminished, probably as the result of a lower population of Cl-/HCO3- exchangers in the apical membrane as compared with the normal cells. Some segments of the normal renal tubule are also capable of utilizing CFTR to secrete Cl-, particularly the inner medullary collecting duct. The ability of Madin-Darby canine kidney cells and normal human kidney cortex cells to form cysts in culture and to secrete fluid and the functional similarities between these incompletely differentiated, proliferative cells and developing cells in the intestinal crypt and in the fetal lung have led us to suggest that Cl- and fluid secretion may be a common property of at least some renal epithelial cells in an intermediate stage of development. The genetic defect in ADPKD may not directly affect membrane transport mechanisms but rather may arrest the development of certain renal epithelial cells in an incompletely differentiated, proliferative stage.

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“…Apical mislocation of Na + /K + -ATPase is associated with human polycystic kidney disease (Ogborn et al, 1993;Wilson, 1997;Wilson et al, 1991). The results shown in this report suggest that there is a more complex targeting role for the N-glycans of Na + /K + -ATPase (and other membrane glycoproteins) than has been previously thought.…”

Section: Discussionmentioning

confidence: 30%

Deglycosylation of Na+/K+-ATPase causes the basolateral protein to undergo apical targeting in polarized hepatic cells

Lian¹,

Wu²,

Dao³

et al. 2006

Journal of Cell Science

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Polarized epithelia, such as hepatocytes, target their integral membrane proteins to specific apical or basolateral membrane domains during or after biogenesis. The roles played by protein glycosylation in this sorting process remain controversial. We report here that deglycosylation treatments in well-polarized hepatic cells by deglycosylation drugs, or by site-directed mutagenesis of the N-linked-glycosylation residues, all cause the Na+/K+-ATPase β-subunit to traffic from the native basolateral to the apical/canalicular domain. Deglycosylated β-subunits are still able to bind and therefore transport the catalytic α-subunits to the aberrant apical location. Such apical targeting is mediated via the indirect transcytosis pathway. Cells containing apical Na+/K+-ATPase appear to be defective in maintaining the ionic gradient across the plasma membrane and in executing hepatic activities that are dependent upon the ionic homeostasis such as canalicular excretion.

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Renal tubule Na,K-ATPase polarity in glucocorticoid-induced polycystic kidney disease.

Cited by 14 publications

References 13 publications

Apical Plasma Membrane Mispolarization of NaK-ATPase in Polycystic Kidney Disease Epithelia Is Associated with Aberrant Expression of the β2 Isoform

Apical Plasma Membrane Mispolarization of NaK-ATPase in Polycystic Kidney Disease Epithelia Is Associated with Aberrant Expression of the β2 Isoform

Epithelial Transport in Polycystic Kidney Disease

Deglycosylation of Na+/K+-ATPase causes the basolateral protein to undergo apical targeting in polarized hepatic cells

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