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)

Genetically based polycystic kidney diseases include autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney diseases, nephronophthisis and medullary cystic disease. The PKD1 and PKD2 genes responsible for ADPKD and their respective encoded proteins polycystin-1 and polycystin-2 are under intense study and clues are developing as to their function and roles in the disease process. Structure-function analysis suggests that polycystins form multiprotein complexes with focal adhesion and cell-cell adherens junction proteins, which then initiate intracellular signaling events culminating in regulation of transcription of genes controlling proliferation and differentiation. Although less is known about the PKHD-encoded fibrocystin responsible for ARPKD or about the NPH1-encoded nephrocystin responsible for nephronophthisis, it is proposed that they function in the same cellular pathway involving protein-protein interactions, signal transduction and regulation of gene transcription. ADPKD epithelia are more adherent to collagen, less migratory, fail to recruit FAK to polycystin complexes and show aberrant, persistent expression of the fetal genes Erb-B2 and beta2 subunit of NaK-ATPase after birth. It is suggested that the function of the polycystin complex is to act as a key developmental regulator of renal tubule morphogenesis.
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PMID:The genes and proteins associated with poly-cystic kidney diseases. 1253 90

Autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney disease are characterized by the progressive growth and expansion of cysts or ectatic collecting ducts, respectively, that ultimately destroy the normal renal parenchyma. Evidence from experimental models of ADPKD suggests that transepithelial Na and fluid secretion contribute to cyst growth, yet little is known about solute transport in ARPKD. This purpose of this study was to begin to characterize the expression and polarity of transport proteins involved in vectorial Na movement in ARPKD epithelium. Immunodetectable alpha1 and beta2 subunits of the Na/K-ATPase localized to the apical membrane of collecting duct cysts in tissue sections of human fetal ARPKD nephrectomy specimens and conditionally immortalized cells derived from these cysts. Measurements of transepithelial (22)Na transport performed on monolayers of ARPKD and age-matched collecting tubule (HFCT) cells grown on permeable supports revealed net Na absorption in both models. However, ARPKD cells absorbed Na at a rate approximately 50% greater than that of HFCT. Furthermore, Na absorption in ARPKD cells was partially inhibited by 100 micro M apical amiloride or 1 mM basolateral but not apical ouabain. Northern blot analyses of ARPKD whole kidney and Western immunoblot of ARPKD cells showed approximately twofold greater expression of the alpha-subunit of the epithelial Na channel (ENaC) compared with age-matched controls. These results suggest that, despite the presence of apical Na/K-ATPase, ARPKD cyst-lining cells absorb Na by a pathway that is modestly amiloride-sensitive. Whether Na absorption is mediated by ENaC, perhaps of nonclassical subunit composition, or another amiloride-sensitive transporter remains to be determined.
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PMID:Na transport in autosomal recessive polycystic kidney disease (ARPKD) cyst lining epithelial cells. 1266 Mar 16

Gene therapy has the potential to provide a therapeutic strategy for numerous renal diseases such as diabetic nephropathy, chronic rejection, Alport syndrome, polycystic kidney disease, and inherited tubular disorders. In previous studies using cationic liposomes or adenoviral or retroviral vectors to deliver genes into the kidney, transgene expression has been transient and often associated with adverse host immune responses, particularly with the use of adenoviral vectors. The unique properties of recombinant adeno-associated viral (rAAV) vectors permit long-term stable transgene expression with a relatively low host immune response. The purpose of the present study was to evaluate gene expression in the rat kidney after intrarenal arterial infusion of a rAAV (serotype 2) vector encoding green fluorescence protein (GFP) induced by a cytomegalovirus-chicken beta-actin hybrid promoter. The left kidney of experimental animals was treated with either saline or transduced with rAAV2-GFP (0.125 ml/100 g body wt, 1 x 10(10)/ml infectious units) through the renal artery. A time-dependent expression of GFP was observed in all kidneys injected with rAAV2-GFP, with maximal expression observed at 6 wk posttransduction. The expression of GFP was restricted to cells in the S(3) segment of the proximal tubule and intercalated cells in the collecting duct, the latter identified by co-localization with H(+)-ATPase. No transduction was observed in the glomeruli or the intrarenal vasculature. These studies demonstrate successful transgene expression in tubular epithelial cells, specifically in the S(3) segment of the proximal tubule and intercalated cells, after intrarenal administration of a rAAV vector and provide the impetus for further studies to exploit its use as a tool for gene therapy in the kidney.
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PMID:Gene delivery in renal tubular epithelial cells using recombinant adeno-associated viral vectors. 1266 Mar 29

It has been proposed that autosomal dominant polycystic kidney disease (ADPKD)affected renal epithelial cells undergo a phenotypic transition from a highly differentiated absorptive state to a much less differentiated secretory state during cystogenesis and that this transition is accompanied by loss of epithelial cell polarity and mistargeting of specific membrane proteins. We conducted a detailed evaluation of this hypothesis in the Pkd2WS25/- mouse model of ADPKD. Ultrastructural analysis of Pkd2WS25/- cysts by electron microscopy confirmed that cystic epithelial cells progressively dedifferentiate with cyst enlargement. Immunocytochemical analysis of both early- and late-stage cysts with antibodies directed against Na+-K+-ATPase, Ksp-cadherin, and E-cadherin failed to detect evidence of altered cyst cell polarity. Na+-K+-ATPase and Ksp-cadherin were expressed exclusively on the basolateral membranes (BLM) of epithelial cells in all early cysts. Expression levels of both Na+-K+-ATPase and Ksp-cadherin decreased progressively with the degree of cyst cell dedifferentiation, but neither protein was ever mislocalized. Highly dedifferentiated cysts did not express immunodetectable levels of either Na+-K+-ATPase or Ksp-cadherin. E-cadherin was expressed prominently on the BLM of all cysts. Cysts were subsequently stained with an antibody directed against the secretory isoform of the Na+-K+-Cl- cotransporter NKCC1. NKCC1 expression was detected on the BLM of advanced cysts only. Our data are consistent with a model of progressive cystic epithelial cell dedifferentiation in which fluid accumulation in late-stage cysts is mediated by transepithelial secretion of chloride rather than secretion of sodium by apical Na+-K+-ATPase.
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PMID:Histopathological analysis of renal cystic epithelia in the Pkd2WS25/- mouse model of ADPKD. 1285 Dec 51

Na-K-ATPase, also known as the sodium pump, is a crucial enzyme that regulates intracellular sodium homeostasis in mammalian cells. In epithelial cells Na-K-ATPase function is also involved in the formation of tight junctions through RhoA GTPase and stress fibers. In this review, a new two-step model for the assembly of tight junctions is proposed: step 1, an E-cadherin-dependent formation of partial tight junction strands and of the circumferential actin ring; and step 2, active actin polymerization-dependent tethering of tight junction strands to form functional tight junctions, an event requiring normal function of Na-K-ATPase in epithelial cells. A new role for stress fibers in the assembly of tight junctions is proposed. Also, implications of Na-K-ATPase function on tight junction assembly in diseases such as cancer, ischemia, hypomagnesemia, and polycystic kidney disease are discussed.
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PMID:Role of Na-K-ATPase in the assembly of tight junctions. 1289 Jun 62

Polycystin-1 (PC-1) is the product of the PKD1 gene, which is mutated in autosomal dominant polycystic kidney disease. We show that the Na,K-ATPase alpha-subunit interacts in vitro and in vivo with the final 200 amino acids of the polycystin-1 protein, which constitute its cytoplasmic C-terminal tail. Functional studies suggest that this association may play a role in the regulation of the Na,K-ATPase activity. Chinese hamster ovary cells stably expressing the entire PC-1 protein exhibit a dramatic increase in Na,K-ATPase activity, although the kinetic properties of the enzyme remain unchanged. These data indicate that polycystin-1 may contribute to the regulation of Na,K-ATPase activity in kidneys in situ, thus modulating renal tubular fluid and electrolyte transport.
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PMID:The C-terminal tail of the polycystin-1 protein interacts with the Na,K-ATPase alpha-subunit. 1610 61

In autosomal dominant polycystic kidney disease (ADPKD), cyst formation and enlargement require proliferation of mural renal epithelial cells and the transepithelial secretion of fluid into the cyst cavity. Na,K-ATPase is essential for solute and water transport in ADPKD cells, and ouabain blocks fluid secretion in these cells. By binding to the Na,K-ATPase, ouabain also induces proliferation in some cell types. Surprisingly, it was found that nanomolar concentrations of ouabain, similar to those circulating in blood, induced ADPKD cell proliferation but had no statistically significant effect on normal human kidney (NHK) cells. Ouabain, acting from the basolateral side of the cells, also caused an increase in the level of phosphorylated extracellular signal-regulated kinases (ERK). Mitogen-activated protein kinase kinase (MEK) inhibitor U0126 blocked ouabain-induced ERK activation and cell proliferation, suggesting that ouabain effect is mediated through the MEK-ERK pathway. In contrast to NHK cells, the dose-response curve for ouabain inhibition of Na,K-ATPase activity indicated that approximately 20% of the enzyme in ADPKD cells exhibits a higher affinity for ouabain. The increased ouabain affinity of ADPKD cells was not due to differences in Na,K-ATPase isoform expression because these cells, like NHK cells, possess only the alpha1 and beta1 subunits. The gamma variants of the Na,K-ATPase also are expressed in the cells but are elevated in ADPKD cells. Currently, the basis for the differences in ouabain sensitivity of NHK and ADPKD cells is unknown. It is concluded that ouabain stimulates proliferation in ADPKD cells by binding to the Na,K-ATPase with high affinity and via activation of the MEK-ERK pathway.
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PMID:Ouabain binds with high affinity to the Na,K-ATPase in human polycystic kidney cells and induces extracellular signal-regulated kinase activation and cell proliferation. 1715 36

The exclusive basolateral localization of the Na-K-ATPase in kidney epithelium is a critical aspect of nephron function. It has been suggested that mislocalized delivery of the Na-K-ATPase to the apical surface in autosomal dominant polycystic kidney disease (ADPKD) is due to the inappropriate expression of an alternative isoform of the beta-subunit, the beta(2)-isoform. It has been reported that heterologous expression of this beta(2)-isoform in Madin-Darby canine kidney (MDCK) cells results in apical delivery of the Na-K-ATPase. We created a MDCK cell line containing a tetracycline-inducible promoter and expressed either myc-tagged beta(2)- or flag-tagged beta(1)-subunits to study the surface localization of these beta-subunit isoforms in polarized monolayers. We find that the beta(2)-isoform is targeted to the basolateral surface of the plasma membrane in a polarization pattern indistinguishable from the beta(1)-isoform. However, inclusion of butyrate in the growth medium leads to upregulation of overexpressed beta(1)- or beta(2)-subunits and to their appearance at the apical surface. The beta(2)-isoform expressed in MDCK cells does not assemble into alpha(1)beta(2) heterodimers with the endogenous alpha(1). Our findings demonstrate that expression of the beta(2)-isoform does not lead to apical localization of the Na-K-ATPase in MDCK cells and provides evidence for an unexpected effect of butyrate on the trafficking of Na pump subunits.
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PMID:Selective basolateral localization of overexpressed Na-K-ATPase beta1- and beta2- subunits is disrupted by butryate treatment of MDCK cells. 1734 87

Integrin adhesion receptors are critical for antigen recognition by T cells and for regulated recirculation and trafficking into and through various tissues in the body. T-cell receptor (TCR) signaling induces rapid increases in integrin function that facilitate T-cell activation by promoting stable contact with antigen-presenting cells and extracellular proteins in the environment. In this review, we outline the molecular mechanisms by which the TCR signals to integrins and present a model that highlights four key events: (i) initiation of proximal TCR signals nucleated by the linker for activated T cells (LAT) adapter protein and involving Itk, phospholipase C-gamma1, Vav1, and Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa; (ii) transmission of integrin activation signals from the LAT signalosome to integrins by protein kinase (PK) C and the adapter protein, adhesion and degranulation-promoting adapter protein; (iii) assembly of integrin-associated signaling complexes that include PKD, the guanosine triphosphatase Rap1 and its effectors, and talin; and (iv) reorganization of the actin cytoskeleton by WAVE2 and other actin-remodeling proteins. These events coordinate changes in integrin conformation and clustering that result in enhanced integrin functional activity following TCR stimulation.
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PMID:T-cell receptor signaling to integrins. 1762 44

Endoplasmic reticulum(ER)-associated degradation (ERAD) is an essential process for cell homeostasis and remains not well understood. During ERAD, misfolded proteins are recognized, ubiquitinated on ER and subsequently retro-translocated/dislocated from ER to the 26S proteasome in the cytosol for proteolytic elimination. Polycystin-2 (PC2), a member of the transient receptor potential superfamily of cation channels, is a Ca channel mainly located on ER and primary cilium membranes of cells. Mutations in PC2 are associated with autosomal dominant polycystic kidney disease (ADPKD). The cellular and molecular mechanisms underlying the PC2-associated pathogenesis remain unclear. Here we show that PC2 degradation is regulated by the ERAD pathway through the ubiquitin-proteasome system. PC2 interacted with ATPase p97, a well-known ERAD component extracting substrates from ER, and immobilized it in perinuclear regions. PC2 also interacted with Herp, an ubiquitin-like protein implicated in regulation of ERAD. We found that Herp is required for and promotes PC2 degradation. ER stress accelerates the retro-translocation of PC2 for cytosolic degradation, at least in part through increasing the Herp expression. Thus, PC2 is a novel ERAD substrate. Herp also promoted, to varied degrees, the degradation of PC2 truncation mutants, including two pathogenic mutants R872X and E837X, as long as they interact with Herp. In contrast, Herp did not interact with, and has no effect on the degradation of, PC2 mutant missing both the N- and C-termini. The ERAD machinery may thus be important for ADPKD pathogenesis because the regulation of PC2 expression by the ERAD pathway is altered by mutations in PC2.
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PMID:Polycystin-2 is regulated by endoplasmic reticulum-associated degradation. 1817 78


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