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)

Several rat models of polycystic kidney disease (PKD) have been published. The only rat model of autosomal dominant polycystic kidney disease currently used is the so-called Hannover rat (Han:SPRD cy/+). This model is characterized by a slow progression of uraemia, proteinuria and hyperlipidaemia. Histological changes clearly resemble those seen is human PKD. The localization of Na+/K(+)-ATPase correlating with the phenotype of the cysts--basal in moderately expanded and apical in highly expanded cysts--suggests that the mislocation of the Na+/K(+)-ATPase is involved in the mechanism of cyst expansion rather than formation, and a consequence of cell dedifferentiation rather than an initial event. Of note is a considerable gender difference in disease severity. Disease anticipation or genetic imprinting does not occur. In addition to gender, a number of interventions influence the progression rate: acceleration is noted after unilateral nephrectomy, the induction of acidosis, chloride feeding or an increased protein intake; slowing down of the course occurs after the induction of alkalosis and castration, and after treatment with lovastatin and methylprednisolone. Thus the Han:SPRD cy/+ rat represents the only well-documented rat model of autosomal dominant PKD resembling a number of features of the human disease.
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PMID:Rat models of autosomal dominant polycystic kidney disease. 904 28

A form of autosomal dominant polycystic kidney disease (ADPKD) similar in clinical features to human ADPKD occurs in the Persian cat. We characterized the morphologic and immunohistochemical features of this disease in a colony of affected cats. Complete postmortem examinations were performed on 11 normal and 22 affected cats ranging in age from 3 months to 10 years. Kidneys were evaluated by gross and histologic examinations, ultrastructure, lectin staining, bromodeoxyuridine immunochemistry for labeling index and immunochemistry for distribution of Na/K ATPase. Feline ADPKD was characterized by variable numbers of cysts in the renal cortex and medullar. Ultrastructural examination and lectin staining suggested that cysts arose from proximal and distal nephron segments. Bromodeoxyuridine labeling demonstrated increased proliferation of epithelium lining some cysts in young cats. Immunohistochemical staining showed variable translocation of Na/K ATPase from the basolateral membranes of cyst-lining cells to the cytoplasm or luminal membranes. Cystic renal disease commonly was associated with chronic tubulointerstitial nephritis and hepatobiliary hyperplasia and fibrosis. Focal hyperplasia of renal tubular epithelium, hepatic cysts, and cardiac lesions were present in some cats. Feline ADPKD shares many morphologic and pathogenetic features with human ADPKD.
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PMID:Autosomal dominant polycystic kidney disease in Persian and Persian-cross cats. 906 78

The establishment and maintenance of epithelial polarity is essential for the integrity and function of epithelial organs and is particularly critical in the kidney, where vectorial reabsorption and secretion are effected in different segments of the nephron by the differential polarized insertion of channels, transporters, and related proteins into apical membranes lining the tubule lumen or basolateral membranes adjacent to the interstitium and blood space. Faulty intracellular delivery and polarization of membrane proteins can lead to serious diseases such as cystic fibrosis, I cell disease, and renal cystic diseases. The best understood disease of epithelial polarity is autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in a >462-kDa, developmentally regulated membrane protein, "polycystin." ADPKD cysts are characteristically lined by a single layer of structurally polarized epithelial cells with normal functional intercellular tight junctions but with aberrant polarization of some important membrane proteins. Abnormal apical membrane polarity of biochemically active, ouabain-sensitive Na-K-adenosinetriphosphatase (Na-K-ATPase) in ADPKD cyst epithelia leads to abnormal sodium ion secretion and provides a mechanism for aberrant fluid secretion. In addition, apically mislocated, functional epidermal growth factor (EGF) receptors on cyst epithelia, together with EGF synthesis and secretion into cyst lumens, provide a mechanism for autocrine regulation of increased epithelial cell proliferation in ADPKD. Underlying mechanisms for these abnormalities in polarized distribution of membrane proteins include the aberrant expression of fetal gene products, such as the beta2-subunit of Na-K-ATPase, in ADPKD kidneys. Overexpression of polycystin protein in ADPKD cyst epithelia, low levels restricted to medullary collecting tubules in normal adult kidneys, and high levels in ureteric bud-derived structures in human fetal kidneys further suggest a failure of downregulation of fetal genes as a mechanism for the polarity abnormalities that characterize ADPKD.
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PMID:Epithelial cell polarity and disease. 914 43

Multiple cyst formation with fluid retention is a characteristic structural abnormality in polycystic kidney disease (PKD). Na/K adenosine triphosphatase (ATPase) is a major transporting membrane protein that is ubiquitous in the epithelial cell, which has been thought to be involved in cystogenesis. We have investigated the molecular and histologic basis of Na/K ATPase activity in experimental PKD in vivo. Rats were treated with diphenylthiazole (100 mg/100 gm body weight), and cyst formation was examined histologically. Na/K ATPase activity was measured enzymatically by using a fluorometric method, and reverse transcription-competitive polymerase chain reaction (RT-PCR) analysis was used to quantitate mRNA levels in the isolated single nephron segment. Kidneys were immunostained with subunit-specific antibodies to determine the localization of Na/K ATPase in the epithelial cell. The enzyme activity increased in the cortical collecting duct from 25.9 +/- 3.5 mmol/Lpmol/mm/min to 72.9 +/- 6.8 pmol/mm/min and in the outer medullary collecting duct from 13.0 +/- 3.9 mmol/Lpmol/mm/min to 58.5 +/- 9.8 pmol/mm/min (n = 6, p < 0.01); however, all other segments showed no significant changes. No significant alternation in alpha 1- and beta 1-subunits of Na/K ATPase mRNA levels was observed by competitive PCR assay in either segment. The enzyme was stained at the basolateral membrane even in the cystic tubules. Na/K ATPase activity was up-regulated in the cyst-formed kidney, but this was not accompanied with transcriptional up-regulation. Increased Na/K ATPase activity at normal locations may play a role in abnormal net fluid transport in the development and progression of experimental PKD.
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PMID:A role for Na/K adenosine triphosphatase in the pathogenesis of cyst formation in experimental polycystic kidney disease. 914 48

Polycystic kidney disease progresses more rapidly in men than in women. To investigate the basis for this sexual dimorphism, we exposed Madin-Darby canine kidney (MDCK) cells grown on collagen-coated cell culture inserts to control media, or to estradiol or testosterone (1 nM-1 microM). Compared to control and estradiol-treated cells, testosterone stimulated fluid secretion in a dose-dependent manner, enhancing fluid secretion 4.8-fold at 1 nM and 19.7-fold at 1 microM (0.59 +/- 0.18 vs. 0.03 +/- 0.01 microliter/cm2/hr, P < 0.001). Chloride transport paralleled fluid secretion. Testosterone increased cellular cyclic AMP levels 3.2-fold at 1 nM and 12.3-fold at 1 microM (81.3 +/- 30.7 vs. 6.6 +/- 3.3 pmol/mg protein, P < 0.001). GDP beta S (500 microM), an inhibitor of Gs, and 2',3'-dideoxyadenosine (10 microM), an inhibitor of the catalytic subunit of adenylate cyclase, suppressed testosterone-induced fluid and solute secretion. Neither testosterone nor estradiol had any effect on microsomal Na,K-ATPase activity, cellular proliferation or cellular total protein content. Our studies show that testosterone stimulates fluid secretion and solute transport by MDCK cells by increasing cAMP generation. In vivo, testosterone may contribute to cyst expansion by enhancing fluid secretion. This observation may help explain the worse prognosis of polycystic kidney disease observed in men.
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PMID:Effects of sex hormones on fluid and solute transport in Madin-Darby canine kidney cells. 915 Apr 70

Despite the recent positional cloning of genes responsible for autosomal dominant polycystic kidney disease (ADPKD), the exact pathogenetic mechanisms underlying this disorder are still unclear. To learn more about cyst formation, we investigated cell differentiation and cell polarity in the Han:SPRD (cy/+) rat between 21 days and 60 wk of age. At early stages of cyst development, alkaline phosphatase, aquaporin-1, NaSi-1 cotransporter, and Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) were expressed normally. Clusterin mRNA was only sparsely expressed at the onset of cystic degeneration and increased thereafter, being highest in noncystic nephron segments. In cyst wall cells, clusterin on the one hand and alkaline phosphatase, aquaporin-1, NaSi-1-cotransporter, and Na(+)-K(+)-ATPase on the other were expressed in a mutually exclusive fashion. No change in cell polarity could be observed at any stage. Our data therefore argue against a change in cell polarity and against an early arrest in normal tubular development during cyst formation in the Han:SPRD (cy/+) rat model of ADPKD but favor the hypothesis that tubular epithelia develop in an orderly fashion and degenerate thereafter.
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PMID:Differentiation and cell polarity during renal cyst formation in the Han:SPRD (cy/+) rat, a model for ADPKD. 932 8

Preparation of kidney proximal tubules in suspension allows the study of receptor-mediated endocytosis, protein reabsorption, and traffic of endosomal vesicles. The study of tubular protein transport in vitro coupled with that of the function of endosomal preparation offers a unique opportunity to investigate a receptor-mediated endocytosis pathway under physiological and pathological conditions. We assume that receptor-mediated endocytosis of albumin in kidney proximal tubules in situ and in vitro can be regulated, on the one hand, by the components of the acidification machinery (V-type H+-ATPase, Cl(-)-channel and Na+/H+-exchanger), giving rise to formation and dissipation of a proton gradient in endosomal vesicles, and, on the other hand, by small GTPases of the ADP-ribosylation factor (Arf)-family. In this paper we thus analyze the recent advances of the studies of cellular and molecular mechanisms underlying the identification, localization, and function of the acidification machinery (V-type H+-ATPase, Cl(-)-channel) as well as Arf-family small GTPases and phospholipase D in the endocytotic pathway of kidney proximal tubules. Also, we explore the possible functional interaction between the acidification machinery and Arf-family small GTPases. Finally, we propose the hypothesis of the regulation of translocation of Arf-family small GTPases by an endosomal acidification process and its role during receptor-mediated endocytosis in kidney proximal tubules. The results of this study will not only enhance our understanding of the receptor-mediated endocytosis pathway in kidney proximal tubules under physiological conditions but will also have important implications with respect to the functional consequences under some pathological circumstances. Furthermore, it may suggest novel targets and approaches in the prevention and treatment of various diseases (cystic fibrosis, Dent's disease, diabetes and autosomal dominant polycystic kidney disease).
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PMID:Receptor-mediated endocytosis in kidney proximal tubules: recent advances and hypothesis. 958 51

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic adenosine monophosphate dependent, low-conductance chloride channel found on the apical plasma membrane of secretory epithelia. Surprisingly, since cystic fibrosis patients have no kidney phenotype, CFTR is highly expressed in the kidney, present from 12 weeks of gestation in the human metanephric kidney. As well as the mature, full-length, 165-kD wild-type protein (WT-CFTR) associated with renal tubule plasma membranes, intracellular, partially glycosylated forms are also seen in normal kidneys. In addition, a kidney-specific splice variant of CFTR translates a cytoplasmic truncated protein (TNR-CFTR), apparently associated with a specific small endosomal population, and is predominantly expressed in the renal medulla. WT-CFTR and TNR-CFTR show different patterns of developmental regulation, WT-CFTR being the major form expressed early in metanephric development when it is localized at the apical plasma membrane of developing collecting tubules. By contrast, TNR-CFTR expression increases with gestational age, reaching adult levels at 23 weeks. Evidence suggests that WT-CFTR plays a role in chloride secretion into the apical lumen of normal distal tubules. In autosomal dominant polycystic kidney disease, normally targeted CFTR at the apical plasma membrane in association with mislocalized Na-K-ATPase may result in abnormal fluid secretion into cysts. Similar colocalization of WT-CFTR and Na-K-ATPase at the apical plasma membranes is found in collecting tubules during development when it is speculated to play a role in the initiation of opening of the tubule lumen.
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PMID:Cystic fibrosis transmembrane conductance regulator in the kidney: clues to its role? 1045 15

Kidney injury molecule-1 (Kim-1) is a type 1 membrane protein maximally upregulated in proliferating and dedifferentiated tubular cells after renal ischemia. Because epithelial dedifferentiation, proliferation, and local ischemia may play a role in the pathophysiology of autosomal dominant polycystic kidney disease, we investigated Kim-1 expression in a mouse model of this disease. In the Pkd2(WS25/-) mouse model for autosomal dominant polycystic kidney disease, cystic kidneys show markedly upregulated Kim-1 levels compared with noncystic control kidneys. Kim-1 is present in a subset of cysts of different sizes and segmental origins and in clusters of proximal tubules near cysts. Kim-1-expressing tubular cells show decreased complexity and quantity of basolateral staining for Na-K-ATPase. Other changes in polarity characteristic of ischemic injury are not present in Kim-1-expressing pericystic tubules. Polycystin-2 expression is preserved in Kim-1-expressing tubules. The interstitium surrounding Kim-1-expressing tubules shows high proliferative activity and staining for smooth muscle alpha-actin, characteristic of myofibroblasts. Although the functional role of the protein in cysts remains unknown, Kim-1 expression in tubules is strongly associated with partial dedifferentiation of epithelial cells and may play a role in the development of interstitial fibrosis.
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PMID:Kidney injury molecule-1 expression in murine polycystic kidney disease. 1238 82

The effects of the ERK pathway on electrogenic transepithelial Na(+) absorption by renal collecting duct cells were determined. Approximately 90% of the unstimulated short-circuit current (15 +/- 1 microA/cm(2), n = 10) across conditionally immortalized murine collecting duct epithelial cells (mCT1) is amiloride sensitive and is likely mediated by apical epithelial Na(+) channels. Chronic exposure (24 h) of the epithelial monolayers to either EGF (50 ng/ml) or transforming growth factor-alpha (TGF-alpha; 20 ng/ml) reduced amiloride-sensitive short-circuit current by >60%. The inhibitory effect of EGF on Na(+) absorption was not due to inhibition of basolateral Na(+)-K(+)-ATPase, because the pump current elicited by permeabilization of apical membrane with nystatin was not reduced by EGF. Chronic exposure of the mCT1 cells to EGF (20 ng/ml, 24 h) elicited a 70-85% decrease in epithelial Na(+) channel subunit mRNA levels. Exposure of mCT1 cells to either EGF (20 ng/ml) or PMA (150 nM) induced rapid phosphorylation of p42/p44 (ERK1/2) and pretreatment of the monolayers with PD-98059 (an ERK kinase inhibitor; 30 microM) prevented phosphorylation of p42/p44. Similarly, pretreatment of mCT1 monolayers with PD-98059 prevented the EGF- and PMA-induced inhibition of amiloride-sensitive Na(+) absorption. The results of these studies demonstrate that amiloride-sensitive Na(+) absorption by renal collecting duct cells is regulated by the ERK pathway. This pathway may play a role in alterations in ion transport that occur in polycystic kidney disease.
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PMID:Epidermal growth factor inhibits amiloride-sensitive sodium absorption in renal collecting duct cells. 1238 7


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