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)

Polycystic kidney disease (PKD), in which epithelial cysts arise from or instead of normal renal tubules, is one of the most common genetic diseases. It has both autosomal dominant and autosomal recessive inheritance in humans and in experimental animals. Epithelial cells lining the cysts have an increased rate of proliferation, abnormal polarity of Na-K-adenosinetriphosphatase, which is localized to apical and sometimes lateral membrane domains, and an abnormal extracellular matrix. One hypothesis that explains the simultaneous acquisition of these characteristics as the result of several different genetic mutations is that cell-matrix interactions, which are known to regulate cell proliferation and cell polarity, are altered in PKD. I have created immortalized renal epithelial cell lines from C57Bl/6Jcpk mice with PKD, an autosomal recessive trait in these animals, and from their phenotypically normal littermates. Using these cell lines, I show that polycystic cells have increased adhesion to collagens and laminin mediated by an integrin. These results demonstrate that cell-matrix interactions are defective in PKD and suggest that these interactions may be involved in the abnormalities of cell polarity and cell proliferation seen in these disorders.
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PMID:Murine polycystic kidney epithelial cell lines have increased integrin-mediated adhesion to collagen. 752 86

Apical mislocation of the ubiquitous transport enzyme Na,K-ATPase has been implicated as a feature of cyst development in in vitro studies of human polycystic kidney disease (PKD) epithelia. We undertook an immunohistochemical study of murine glucocorticoid-induced PKD, the pcy mouse, the cpk mouse, and the diphenylthiazole (DPT)-induced rat models of PKD to determine if this feature was common to these models of cyst development. Distribution of Na,K-ATPase was determined with a polyclonal anti-Na,K-ATPase antibody and a nickel-silver-enhanced peroxidase color development system. Results were documented objectively with densitometric techniques. Control animals appropriate to the age, strain, and species of the experimental groups demonstrated the expected polar distribution of Na,K-ATPase to the basolateral surface. This distribution was more marked in mature animals. Tubular dilatation and cystic change, however, were associated with increased apical Na,K-ATPase in all models. The murine models demonstrated decreased basolateral staining for Na,K-ATPase compared with controls, although this was not a feature of the DPT rat model. Abnormal location of Na,K-ATPase is a shared feature of a variety of animal models and human PKD. This may contribute to abnormal fluid and electrolyte flux favoring cyst formation or may represent expression of a less differentiated renal tubule epithelial phenotype.
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PMID:Renal tubule Na,K-ATPase polarity in different animal models of polycystic kidney disease. 762 41

The prevalence and severity of polycystic kidney disease (PKD) induced by glucocorticoids in mice can be predicted by a mathematical "threshold" model. We studied the relationship between Na-K ATPase activity and cyst formation in C3H (low threshold for PKD) and DBA mice (high threshold). There was no difference in Na-K ATPase induction by 200 mg/kg methyl prednisolone acetate (MPA) (C3H; 97.4 nmol NADH/min/mg protein: DBA; 94.2 nmol NADH/min/mg protein). C3H mice demonstrated greater cyst formation than DBA animals as measured by area (20.1% relative area vs 13.9%, p < 0.05) or by calculated volume (7.4% relative volume vs 2.3%, p < 0.001). Significant relationships were seen between Na-K ATPase activity and logarithmically transformed area data in C3H animals and with cyst volume in both strains. Na-K ATPase activity is related to cyst formation in glucocorticoid induced PKD, but the level of Na-K ATPase activity is not a determinant of the threshold for glucocorticoid induced PKD.
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PMID:Na-K ATPase activity in murine glucocorticoid induced polycystic kidney disease in vivo. 768 65

Recently, it has been reported that Na,K-ATPase in the renal epithelia of human autosomal dominant polycystic kidney disease and cpk mouse, a murine model of autosomal recessive polycystic kidney disease, mislocates to apical plasma membrane and that mislocated Na,K-ATPase causes the cyst formation. Whether the DBA/2FG-pcy mice, which are presumably a suitable model for autosomal dominant polycystic kidney disease, also exhibit the reversal polarity of Na,K-ATPase localization was examined. Kidneys of newborn DBA/2FG-pcy mice, and those at early and late stages of cyst development were examined by immunohistochemical techniques. At any stage, abnormal distribution of Na,K-ATPase on the apical membranes of tubular epithelial cells could not be detected. It is suggested that cysts can be formed without reversed polarity of Na,K-ATPase distribution in pcy mice.
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PMID:Sodium pump distribution is not reversed in the DBA/2FG-pcy, polycystic kidney disease model mouse. 791 57

The Han:SPRD rat model for inherited polycystic kidney disease (PKD) was characterized (clinical parameters, morphology, immunohistochemistry and in situ hybridization). Homozygous animals died of uremia after three to four weeks with severe cystic transformation of virtually all nephrons and collecting ducts (serum urea: 616 +/- 195 mg/dl; kidney-to-body weight ratio: > 20%). In heterozygotes, slow progression of the disease led to death between the 12th and 21st month (median: 17 months; serum urea levels above 200 mg/dl). Kidney enlargement was moderate, and cysts were restricted to the cortex and outer medulla. Immunohistochemical markers showed that approximately 75% of the cysts were derived from the proximal tubule. Cystic transformation started in the proximal tubule with a sharp onset of basement membrane alteration and a loss of epithelial differentiation restricted to small focal areas. In these areas, alpha 1(IV) collagen and laminin B1 mRNA were enhanced as revealed by isotopic and non-isotopic in situ hybridization. Fibroblasts underlying the affected tubular portions were involved in matrix overexpression resulting in subepithelial accumulation of immunoreactive collagen IV and laminin. In later stages of cystic transformation distal nephron segments were affected as well. A reversal in epithelial polarity as judged from Na,K-ATPase-immunoreactivity was not observed. Renal immunoreactive renin-status was significantly decreased. Hematocrit was lowered in heterozygotes (40.4 +/- 5.8 vol% compared to 46.7 +/- 1.99 vol% in controls; P < 0.05) and total renal EPO mRNA was reduced to 36 +/- 14% of the mean value of control animals, whereas serum EPO levels were not significantly altered. We conclude that the Han:SPRD rat is a useful model for the study of human ADPKD since both diseases are similar in several aspects. The model is particularly suitable for the study of epithelial-mesenchymal interactions at the beginning of tubular cystic transformation.
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PMID:Characterization of the Han:SPRD rat model for hereditary polycystic kidney disease. 793 31

Renal cysts are central pathological features in a number of human congenital and acquired diseases, and produce significant morbidity and mortality. This review describes our laboratory's efforts to identify specific alterations in epithelial cell polarity and differentiation associated with renal tubular cyst formation and progressive enlargement. Studies in a murine model of human autosomal recessive polycystic kidney disease, the C57BL/6J cpk/cpk (CPK) mouse have demonstrated quantitative (increased activity) and qualitative (apical membrane distribution) alterations in Na+,K(+)-adenosine triphosphatase activity that mediate tubular cyst formation. Proximal tubular cyst formation in CPK kidneys is characterized by increased activity of a basolateral Na+,K(+)-ATPase, which drives organic anion secretion and consequent tubular fluid secretion. In contrast, collecting tubule cyst formation is characterized by increased apical membrane Na+,K(+)-ATPase expression, which may be a marker of the relatively undifferentiated phenotype of cyst lining cells. If such apically expressed enzyme is active, it may have pathogenic import in collecting tubule cyst formation and enlargement by mediating net basal to apical vectorial solute and fluid transport.
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PMID:Epithelial polarity and differentiation in polycystic kidney disease. 814

In the kidney, polarized epithelial cells play critical roles in ion, fluid and solute reabsorption from the ultrafiltrate to the blood supply. Detailed analysis of protein distributions has revealed that ion channels, transporters and pumps are restricted to distinct domains of the plasma membrane that face either the ultrafiltrate (apical membrane) or the blood supply (basal-lateral membrane). The importance of the development and maintenance of the polarized distributions of these proteins in renal epithelia for normal cell function is demonstrated by the fact that several disease states are characterized by abnormal distributions of proteins; for example in polycystic kidney disease, Na+/K(+)-ATPase has been detected in the apical and lateral membranes, compared with normal cells where Na+/K(+)-ATPase is localized in the basal-lateral membrane domain. Recent studies indicate that the development of restricted distributions of proteins at the cell surface of Madin Darby canine kidney epithelial cells is determined by direct sorting of proteins in the trans Golgi network into vesicles that are delivered vectorially to either the apical or basal-lateral membrane. Upon arrival at the plasma membrane, some proteins, such as Na+/K(+)-ATPase, may be selectively retained by binding to the membrane cytoskeleton.
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PMID:Regulation of cell surface polarity in renal epithelia. 825 31

Cyst formation in polycystic kidney disease (PKD) involves proliferation of cyst lining epithelial and changes in trans-epithelial fluid and electrolyte transport. In vitro studies have suggested that mislocation of Na,K-ATPase to the apical tubular surface may be an important component of cyst fluid transport. We undertook in vivo studies of Na,K-ATPase location using the "threshold" murine model of glucocorticoid-induced PKD (GIPKD). Using histological, immunohistochemical, and densitometric techniques, we compared cyst formation and the cellular location of Na,K-ATPase in suckling C3H (low threshold for GIPKD) and DBA (high threshold) mice given an inducing dose of 200 mg/kg methylprednisolone acetate. As expected, C3H mice demonstrated greater cyst formation as measured by proportion of section area occupied by the tubule lumen (26.7% vs 15.5%; p < 0.001). Cyst formation was associated with increased Na,K-ATPase staining and increased apical Na,K-ATPase location. MPA treatment in C3H mice resulted in apical staining that exceeded basolateral staining (35.3% of reference window vs 29.8%; p < 0.001). The relatively GIPKD-resistant DBA mice did not show such change in Na,K-ATPase location. These immunohistochemical studies suggest a role for Na,K-ATPase in renal cyst formation.
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PMID:Renal tubule Na,K-ATPase polarity in glucocorticoid-induced polycystic kidney disease. 838 15

We have sought to determine the mechanisms driving fluid secretion by the cystic epithelium in autosomal dominant polycystic kidney disease (ADPKD). We have performed in vitro experiments on intact cysts dissected from discarded ADPKD kidneys, on monolayers of cells cultured from the cystic epithelium and on microcysts clonally derived from single cultured cells. These preparations absorb fluid in the control state but secrete fluid in response to native cyst fluid, to adenylate cyclase agonists and to permeant analogues of cAMP. Measurements of short-circuit current and transepithelial voltage in the monolayers indicate that anion secretion must drive the fluid secretion. Fluid secretion by the intact cysts was inhibited by basolateral application of ouabain but not by apical application. The effect of ouabain on fluid secretion and short-circuit current in the monolayers followed the same pattern. Thus the functional Na,K-ATPase enzyme complex is located only in the basolateral membrane of the cystic cells and serves to maintain the transmembrane chemical and electrical gradients that drive anion secretion by other transport mechanisms. Fluid secretion and short-circuit current in the cultured monolayers was inhibited by the basolateral application of the Na-K-2Cl cotransporter inhibitors, bumetanide and furosemide, and by apical application of the chloride channel blocker, diphenylamine-2-carboxylate (DPC). These data suggest that chloride is the anion that is actively secreted. Preliminary experiments utilizing the monolayers and the microcysts and measuring cell chloride concentration and chloride efflux across the apical membrane support this conclusion. Other preliminary data indicate that the cystic fibrosis transmembrane conductance regulator is present in the apical membrane. Thus active chloride transport generates fluid secretion by the cystic epithelium.
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PMID:Mechanisms of fluid secretion by polycystic epithelia. 874 60

The kidneys of patients with autosomal dominant polycystic kidney disease become massively enlarged due to the progressive expansion of myriad fluid-filled cysts. The epithelial cells that line the cyst walls are responsible for secreting the cyst fluid, but the mechanism through which this secretion occurs is not well established. Recent studies suggest that renal cyst epithelial cells actively secrete Cl across their apical membranes, which in turn drives the transepithelial movement of Na and water. The characteristics of this secretory flux suggest that it is dependent upon the participation of an apical cystic fibrosis transmembrane conductance regulator (CFTR)-like Cl channel and basolateral Na,K-ATPase. To test this hypothesis, we have immunolocalized the CFTR and Na,K-ATPase proteins in intact cysts and in cyst epithelial cells cultured in vitro on permeable filter supports. In both settings, cyst epithelial cells were found to possess Na,K-ATPase exclusively at their basolateral surfaces; apical labeling was not detected. The CFTR protein was present at the apical surfaces of cyst epithelial cells that had been stimulated to secrete through incubation in forskolin. CFTR was detected in intracellular structures in cultured cyst epithelial cells that had not received the forskolin treatment. These results demonstrate that the renal epithelial cells that line cysts in autosomal dominant polycystic kidney disease express transport systems with the appropriate polarity to mediate active Cl and fluid secretion.
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PMID:Immunolocalization of ion transport proteins in human autosomal dominant polycystic kidney epithelial cells. 881 77


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