Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital polycystic kidney disease is characterized by the formation of large fluid-filled cysts in kidney tubules. It has been postulated that increased epithelial cell proliferation and altered transtubular fluid transport are necessary for cyst formation. To address the latter problem, we have studied the plasma membrane distribution of the alpha 1 and beta 1 subunits of Na+/K(+)-ATPase during progressive stages of proximal and collecting tubular cyst formation in the CPK mouse, a murine model of autosomal recessive polycystic kidney disease. In both control and cystic proximal tubules, Na+/K(+)-ATPase distribution was restricted to the basal-lateral membrane of cells. However, in newborn through day 5 kidney tissue, 16% of control vs. 47% of cystic outer cortical, 6% of control vs. 46% of cystic inner cortical, and 2% of control vs. 63% of cystic medullary collecting tubules demonstrated apical and lateral membrane distribution of Na+/K(+)-ATPase. In all nephrogenic zones, the percentage of control or cystic collecting tubules demonstrating apical membrane distribution of Na+/K(+)-ATPase decreased over time, but the percentage of cystic collecting tubules with apical membrane Na+/K(+)-ATPase remained significantly greater than in developmentally matched controls. No alterations in the normal distributions of other apical or basal-lateral membrane marker proteins were noted at any stage of control or cystic proximal or collecting tubule development. We conclude that apical-lateral membrane Na+/K(+)-ATPase expression is a normal transient feature of early collecting tubule development. However, apical membrane Na+/K(+)-ATPase persists in cystic kidneys, suggesting that such expression may be a manifestation of the relatively undifferentiated phenotype of epithelial cells lining collecting tubule cysts. The persistence of apical membrane Na+/K(+)-ATPase, if the enzyme is functional, may have pathogenic important in abnormal transtubular fluid transport in polycystic kidney disease.
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PMID:Abnormal sodium pump distribution during renal tubulogenesis in congenital murine polycystic kidney disease. 132 37

Tubular basement membrane (BM) changes (dysmorphogenesis), cell proliferation, and fluid accumulation related to the altered location of Na,K-ATPase are purported essential key events in the development and progression of renal cysts. These changes were assessed daily in Phenol II (2-amino-4-hydroxyphenyl-5-phenyl thiazole)-treated rats, which rapidly develop marked and progressive cystic change of all collecting tubules (CT). At Day 1, 12% of CT were cystic and their BM were thickened severalfold. At Day 4, 30% of CT were cystic and their BM remained thickened. BM of cystic tubules showed decreased staining for heparan sulfate proteoglycan and increased staining for fibronectin. Proliferation, as determined by (3H)thymidine, incorporation, was not significant until Day 2 and involved cystic and noncystic tubular cells as well as interstitial cells. As cystic changes progressed, cell proliferation decreased. By immunohistochemistry, the altered location of Na,K-ATPase in epithelial cells lining cysts was primarily detected after Day 2 and consisted of focal loss from basal and/or lateral cell membranes and localization in the cell cytoplasm. Only rarely was Na,K-ATPase localized to the apical cell membrane. After the removal of Phenol II, cystic tubular cells, BM, and Na,K-ATPase returned to normal. Thus, in this model of polycystic kidney disease, initial cyst formation occurred in tandem with BM structural change whereas cell proliferation and altered location of Na,K-ATPase occurred after the appearance of cysts.
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PMID:Sequential tubular cell and basement membrane changes in polycystic kidney disease. 132 61

Recent advances in the basic mechanisms of developmental biology have started to shed new light on the mechanisms of nephrogenesis. The kidney is the only epithelial organ that starts as mesenchyme and converts to epithelium. It appears that the mesenchyme is composed of stem cells that are able to form glomeruli and proximal and distal tubules under the inductive influences of the ureteric bud. Epithelial cells cultured in a three-dimensional matrix could be induced to form tubules under the influence of a soluble factor from fibroblasts. This factor was identified as scatter factor or hepatocyte growth factor. Polycystic kidney disease appears to be a developmental renal disease in which a basolateral protein, the Na/K ATPase, is mistargeted to the apical and lateral membranes.
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PMID:Cellular and molecular mechanisms of renal development and tubulogenesis. 136 31

The induction of polycystic kidney disease (PKD) by glucocorticoids in newborn mice behaves as a "threshold" trait, with prevalence of PKD varying in different inbred strains after exposure to an inducing steroid. C3H mice (low threshold for PKD) demonstrated greater specific dexamethasone binding than DBA mice (high threshold) on the second day of life. Treatment with methylprednisolone acetate (MPA), a cyst-inducing steroid, down regulated dexamethasone binding earlier than in DBA mice. C3H mice demonstrated greater whole kidney homogenate Na-K ATPase activity than DBA mice within 24h of MPA injection. Specific renal glucocorticoid binding may be a regulator of threshold for murine glucocorticoid induced PKD. Our findings support in vitro evidence that glucocorticoid induced Na-K ATPase activity during critical periods of nephron development is an important regulatory point of this model.
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PMID:Ontogeny of dexamethasone binding and sodium potassium ATPase activity in experimental murine polycystic kidney disease. 165 92

The usefulness of various segment and cell-type specific antibody, lectin and functional markers in the study of cystic renal lesions was evaluated. For this purpose, kidneys from recessive polycystic kidney disease (RPKD), thought to involve mainly the collecting ducts, and cystic kidneys of Meckel's syndrome (MS), which show dilation randomly along the nephron, were studied. The segment (and differentiation-stage)-specific anti-brush-border (specific for proximal tubules) antibodies stained morphologically normal proximal tubules, failed to react with cyst wall epithelium in RPKD, but readily stained some cysts in MS. Immunostaining for Tamm-Horsfall glycoprotein (distal tubules) similarly revealed normal tubular profiles, and also stained moderately dilated tubules, but not the large cysts in either disease type. Lectin markers of the distal tubules and collecting ducts (peanut agglutinin, Helix pomatia agglutinin and Dolichos biflorus agglutinin) reacted with both dilated tubules and with the cyst walls in RPKD and Meckel kidneys, suggesting that in RPKD, the dilations also occur in the distal nephron in addition to the collecting duct, and in MS in any part of the renal tubule. The cell type-specific functional marker of the collecting duct, anti-NaK-ATPase reactivity (found in principal cells) could be seen in RPKD but not in Meckel kidney cysts, suggesting a minor involvement of principal cells in MS. Consistent with this, only occasional carbonic anhydrase (found in intercalated cells) or band 3 (bicarbonate-chloride exchanger molecule of intercalated cells) of collecting ducts positive cells in the cysts could be seen, suggesting that intercalated cells are only sparsely seen in these lesions. The results show the usefulness of a panel of independent markers in studying the segment, cell-type and function-specific features of renal cystic lesions as a basis for their classification.
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PMID:Polycystic disease of the kidney. Evaluation and classification based on nephron segment and cell-type specific markers. 169 Mar 15

In an attempt to isolate candidate genes for autosomal dominant polycystic kidney disease, a number of CpG-rich islands have been identified from a region defined genetically as the site of disease mutations. Genomic fragments adjacent to one of these islands were used to isolate cDNAs from both HeLa cells and cultured cystic epithelium that encode a 155-amino acid peptide having four putative transmembrane domains. The corresponding transcript was found in all tissues tested but was most abundant in brain and kidney. Potential control response elements were identified in the genomic region 5' to the initiation codon. The deduced amino acid sequence has 93% similarity to the 16-kDa proteolipid component that is believed to be part of the proton channel of the vacuolar H(+)-ATPase. Possible roles for a mutated proton channel in the pathogenesis of cystic disease were considered. However, sequencing of cDNAs corresponding to both alleles of an affected individual revealed no differences in the deduced amino acid sequence. Moreover, transcript size and abundance were not altered in cystic kidney.
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PMID:CpG island in the region of an autosomal dominant polycystic kidney disease locus defines the 5' end of a gene encoding a putative proton channel. 170 39

Human polycystic kidney disease (PKD) epithelia were successfully grown in culture and expressed abnormal characteristics. Cysts lining epithelia of superficial and deep cysts were microdissected and compared to individual normal human proximal straight tubules (PST) and cortical collecting tubules (CCT) grown in defined media. PKD cyst epithelia differed from normal renal tubular epithelia in growth patterns and structural and functional properties. PKD epithelia grew more rapidly and showed cyst-like areas in otherwise confluent monolayers. Polygonal and elongate cells contained an epithelial-specific cytokeratin antigen and had polarized morphology. An extremely abnormal basement membrane morphology was seen and consisted of some banded collagen and numerous unique blebs or spheroids. These blebs were apparently extruded from intracellular vacuoles and stained with ruthenium red, suggesting a proteoglycan component. Cytochemistry of marker enzymes demonstrated the presence of NaK-ATPase and alkaline phosphatase, but a lack of gamma-glutamyl transpeptidase. The response of adenylate cyclase activity to vasopressin, parathyroid hormone, and forskolin was significantly diminished in PKD cells as compared to PST and CCT. These studies suggest a defect in cell growth and basement membrane synthesis in human PKD. Cultured PKD epithelia provide a new tool for the study of the pathogenesis of this disease.
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PMID:A new method for studying human polycystic kidney disease epithelia in culture. 243 Nov 89

Recent studies in a murine model of genetically-determined polycystic kidney disease, the CPK mouse, have suggested that alterations in renal Na-K ATPase activity in concert with tubular epithelial hyperplasia have pathogenic import in proximal tubular cyst formation. In the current study, we therefore studied the relative roles of Na-K ATPase activity, tubular epithelial hyperplasia, and basal lamina alterations during in vitro modulation of proximal tubular cyst regression during serum-free organ culture of newborn CPK kidneys. Under basal in vitro conditions, regression of CPK proximal tubular cysts was demonstrated in association with progressive decreases in Na-K ATPase activity and tubular epithelial hyperplasia. The pattern of proximal tubular cyst regression was modified by: a) Na-K ATPase activity induction with triiodothyronine, which promoted proximal tubular cystogenesis; and b) Na-K ATPase activity inhibition with ouabain, which blocked the effects of T3 on the process of cyst formation. Modulation of proximal tubular cystogenesis by Na-K ATPase induction and inhibition were accomplished without significant changes in proximal tubular epithelial hyperplasia or expression of basal lamina components. We conclude that increased Na pump activity may have a significant role in proximal tubular cyst formation and progressive enlargement in the CPK mouse.
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PMID:In vitro modulation of tubular cyst regression in murine polycystic kidney disease. 255 82

In the current study, the pathogenesis of proximal tubular cyst formation was studied in an animal model of polycystic kidney disease, the CPK mouse. The specific roles of (a) sodium-potassium adenosine triphosphatase (Na-K ATPase) activity, determined by an enzyme-linked kinetic microassay, (b) proximal tubular epithelial hyperplasia, determined by calculation of mitotic indices, and (c) altered proximal tubular basal lamina formation, determined by immunohistological localization of basal lamina glycoproteins, were investigated at progressive developmental stages of CPK proximal tubular cyst formation. Increases in renal Na-K ATPase were present at the earliest fetal stages of proximal tubular cyst formation, and subsequently paralleled the course of proximal tubular cyst progression. Proximal tubular epithelial hyperplasia, although not present at the earliest stages of cyst formation, was a consistent feature of progressive proximal tubular cystic enlargement. Abnormalities in basal lamina glycoprotein expression were not present at any stage of proximal tubular cyst development. We conclude that increased Na-K ATPase and tubular epithelial hyperplasia are significant features of proximal tubular cyst formation in the CPK mouse.
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PMID:Congenital murine polycystic kidney disease. II. Pathogenesis of tubular cyst formation. 285 68

Altered membrane polarity has been proposed as an important pathogenetic factor in the development of renal cysts in polycystic kidney disease. To determine whether this alteration in epithelial phenotype is a primary or secondary phenomenon, we examined the epithelial membrane polarity of SBM transgenic mice, in which epithelial proliferation mediated by the c-myc oncogene is an established primary event. Kidneys from 32 transgenic mice and 10 age-matched controls from fetal to adult age were immunostained with antibodies to Na,K-ATPase, fodrin, ankyrin, E-cadherin, and tubule segment-specific lectins. In normal control mice, Na,K-ATPase localization was apical in fetal kidneys but became translocated to the basolateral membrane at maturity. Early microcysts in fetal transgenic kidneys displayed similar (95 to 100%) apical Na,K-ATPase. In young and newborn transgenic mice (1 to 8 days of age), Na,K-ATPase localization was extremely heterogeneous. Noncystic tubules demonstrated either apical (mean 23 to 28%), basolateral (mean 48 to 58%), mixed (mean 4 to 15%), or absent (mean 10 to 13%) staining for Na,K-ATPase. Apical Na,K-ATPase was more frequently observed in early cysts (mean 55%) in young transgenic mice but became less prevalent in adult mice (mean 22%), where 30% of cysts had basolateral staining, 39% mixed patterns, and 9% absent staining. Macrocysts typically lost all Na,K-ATPase reactivity. At all ages, Na,K-ATPase colocalized well with cytoskeletal proteins ankyrin and fodrin. These heterogeneous patterns of Na,K-ATPase staining indicate that although altered cell polarity is frequent in early cystic epithelium of SBM mice, it is not a prerequisite to cystogenesis or progressive cyst enlargement. In conclusion, our results support the view that altered cystic membrane polarity is not a primary process, but represents the persistence of an immature epithelial phenotype characteristic of proliferative polycystic kidney disease epithelia.
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PMID:Analysis of the role of membrane polarity in polycystic kidney disease of transgenic SBM mice. 749 97


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