Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Procainamide is an organic cation and commonly prescribed drug that is actively secreted into the urine by renal proximal tubules. In order to elucidate further the mechanisms involved in this secretion, [3H]procainamide uptake into dissected S2 segments of superficial proximal tubule cells was studied. Uptake of [3H]procainamide was reduced by hypothermia and in a dose-related manner by the organic cations nonradiolabeled procainamide, cimetidine and quinidine and also by the carbonic anhydrase inhibitors acetazolamide and benzolamide, but not by ouabain. All these drugs were shown previously to inhibit transtubular secretion of [3H]procainamide in isolated perfused proximal tubules. The results of these and our previous studies suggest that 1) organic cations reduce the tubular secretion of each other, in part, by competing for uptake across the basolateral membrane of renal tubule cells, 2) acetazolamide and benzolamide reduce urinary excretion of organic cations, in part, by inhibiting proximal tubular secretion and 3) the potential difference across the basolateral cell membrane (due to activity of Na+-K+-dependent adenosine triphosphatase) is not the only driving force for uptake of organic cations into intact renal tubule cells.
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PMID:Procainamide uptake by rabbit proximal tubules. 682 56

Sodium vanadate is a potent inhibitor of Na-K-adenosine triphosphatase. p-Aminohippurate (PAH) and tetraethylammonium accumulation in rat renal cortical slices was inhibited by vanadate in a dose-dependent manner at medium vanadate concentrations from 10(-6) to 10(-3) M. Inhibition was reversible at vanadate concentrations less than 1.5 x 10(-5) M. The slice content of vanadium (7.5-325 micrometer V/g wt. of tissue) was linearly related to medium vanadate concentrations ranging from 10(-5) to 10(-3) M. The ability of slices to generate glucose and ammonia was not impaired by medium vanadate concentrations up to 5 x 10(-4) M, a concentration that maximally inhibited organic ion accumulation. Increasing medium K+ concentrations potentiated vanadate inhibition of PAH accumulation which correlated with inhibition of sodium pump activity, as determined by 42K+ uptake. Intraperitoneal administration of vanadate (1 or 5 mg V/kg) to rats produced a profound diuresis and natriuresis during the 1st hr. Inhibition of PAH accumulation of renal slices from these rats was related to tissue vanadium concentrations. These data suggest that vanadate exerts its action on proximal tubule transport of PAH via inhibition of Na-K-adenosine triphosphatase.
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PMID:Effects of vanadate on organic ion accumulation in rat renal cortical slices. 691 88

Interleukin-1 (IL-1) causes a diuresis and natriuresis in experimental animals. The natriuresis is due, at least in part, to IL-1 stimulation of prostaglandin E2 (PGE2) synthesis by the inner medullary collecting duct (IMCD), with resultant inhibition of Na(+)-K(+)-adenosine triphosphatase activity. It is unknown whether IL-1 affects other signal transduction systems in the IMCDs that regulate nephron sodium and water reabsorption. Furthermore, indirect evidence suggests that IL-1 inhibits sodium and water transport in other nephron segments. Consequently we examined (1) the effect of IL-1 on cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) accumulation by rat IMCD cells and (2) IL-1 stimulation of signal transduction mechanisms throughout the nephron. IL-1 had no affect on cGMP or arginine vasopressin-dependent (AVP-dependent) or isoproterenol-dependent cAMP accumulation in cultured rat IMCD cells. IL-1 increased PGE2 levels in rabbit IMCD, cortical collecting tubule (CCT), and to a lesser extent, medullary thick ascending limb cells, but had no effect on proximal tubule cells. IL-1 also did not alter AVP-dependent cAMP accumulation in the CCT. The failure of IL-1 to reduce AVP responsiveness in the CCT was not due to culture conditions, because AVP-dependent cAMP accumulation in freshly isolated CCT cells was also not affected by the cytokine but was inhibited by exogenous PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 regulation of collecting duct prostaglandin E2 and cyclic nucleotide accumulation. 819 73

The ultrastructure of renal tubule cells was studied in the European lesser spotted dogfish by the evaluation of thin sections and freeze fracture replicas. Computer-assisted three-dimensional reconstruction of entire nephrons was performed. The distinction of nephron segments and collecting tubule was made using results of previous histological work. The first proximal tubule segment (PI) consists of two subsequent portions, PIa and PIb. PIa is a component of the lateral countercurrent bundle, and PIb, which displays an apical tubulovesicular apparatus and an extended lysosomal compartment, is located in the vicinity of the glomeruli. Rod-shaped intramembrane particles were detected in PIa. The second proximal tubule segment (PII) is a special segment in elasmobranch and teleost fish. PII differs largely from PI in cell morphology and function. The apical cytoplasm was filled with small clear vesicles, and an apical endocytic apparatus was lacking. In the apical cell membrane, rod-shaped particles were revealed by freeze fracture. The apical tight junctions of PI and PII consisted of seven to ten meandering strands. The distal nephron was subdivided into two major segments: early distal tubule (EDT) in the lateral countercurrent bundles and late distal tubule (LDT) in the mesial tissue. The EDT showed marked amplification of basolateral cell membranes. The tight junctions displayed a low number of continuous parallel strands, which is also characteristically found in the diluting segments of other vertebrates. LDT cells showed cytoplasmic studs and rod-shaped intramembraneous particles at the apical cell membrane, thereby resembling type A intercalated cells of collecting duct. The collecting tubule (CT) emerged from the LDT and was part of the countercurrent arrangement inside the lateral bundles. Tight junctions of LDT and CT consisted of many meandering strands in a honeycomb pattern. With immunohistochemistry, binding sites of a polyclonal antibody against an extraplasmic portion of rat gastric H(+)-K(+)-adenosine triphosphatase (ATPase) were observed at the apical cell membrane of PIa, PII, and LDT. From the colocalization of binding sites for the antibody against the transport enzyme with rod-shaped intramembrane particles, we assume that these might be the morphological correlate of gastric H(+)-K(+)-ATPase-like enzyme in the renal tubule.
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PMID:Renal tubule of dogfish, Scyliorhinus caniculus: a comprehensive study of structure with emphasis on intramembrane particles and immunoreactivity for H(+)-K(+)-adenosine triphosphatase. 838 22

The mechanism(s) for uptake of organic cations by renal cortical tubules was (were) examined further. Renal cortical tubules were purified from rat kidneys by a Percoll gradient centrifugation technique. Bicarbonate buffer (Krebs-Henseleit, KHS) conditions were altered, and chemical modulators were used which affect the activity of the basolateral Na+/K+-ATPase. Renal tubule uptake of the achiral organic cation amantadine was determined. The cardiac glycosides digoxin and acetylstrophanthidin and ouabagenin did not alter amantadine uptake by either proximal or distal tubule fragments in KHS. However, ouabain inhibited proximal tubule amantadine uptake in a dose-dependent manner with lower potency than distal tubule amantadine uptake in KHS. Ouabain did not inhibit amantadine tubule uptake in phosphate buffer. However, inhibition of amantadine uptake by ouabain returned in a time-dependent manner upon addition of bicarbonate to the phosphate buffer. Low extracellular sodium or potassium did not alter amantadine uptake by proximal tubules. Hypokalemic and hypokalemic/ hyponatremic conditions decreased the inhibitory potency of ouabain for amantadine uptake by proximal tubules. For distal tubules, both hyponatremic and hypokalemic conditions, alone and together, decreased the inhibitory potency of ouabain, but did not affect amantadine uptake in the absence of ouabain. Hypochloremic conditions decreased affinity for amantadine uptake by distal, but not proximal tubules. No change in maximal transport capacity for amantadine uptake was observed under hypochloremic conditions for either tubule fragment. These studies challenge the widely accepted concept of Na+/ K+-adenosine triphosphatase activity and maintenance of the basolateral membrane potential as rate-limiting steps for the energy-dependent renal tubule uptake of organic cations. Furthermore, these studies suggest a mechanism for ouabain inhibition of organic cation renal tubule uptake that may not involve the Na+/K+-adenosine triphosphatase and may be possibly bicarbonate-dependent.
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PMID:Use of digitalis glycosides to identify the mechanisms of amantadine transport by renal tubules. 866 77

The cytochrome P-450 pathway is capable of metabolizing arachidonic acid to omega- and subterminal hydroxylase metabolites, 16-, 17-, 18-, 19-, and 20-hydroxyeicosatetraenoic acids (P-450 HETEs). We have quantitated, by gas chromatography-mass spectrometry (GC/MS), endogenous HETEs exiting the rabbit isolated perfused kidney elicited by hormonal stimulation. Kidneys were perfused with Krebs-Henseleit solution containing indomethacin (2.8 microM) to prevent further metabolism of HETEs by cyclooxygenase. Phenylephrine (2-3 microM) was added to the perfusate to raise perfusion pressure to approximately 80 mmHg. Angiotensin II (ANG II), arginine vasopressin (AVP), and bradykinin (BK) were injected into the renal artery and perfusates collected throughout the vasoactive response. After addition of an internal standard, deuterated 19-HETE, perfusates were extracted and purified and P-450 HETEs were derivatized for GC/MS analysis. Under basal conditions, 16-, 18-, 19-, and 20-HETEs were released (range: 50-270 pg/ml), 19-HETE being the highest and fivefold greater than 16-HETE, the lowest. Injection of 50 ng ANG II increased by two- to sixfold P-450 HETE release associated with an increase of 40 +/- 11 mmHg in perfusion pressure. An equipressor dose of AVP (50 ng) did not release P-450 HETEs nor did a 5-micrograms dose of the vasodilator peptide BK, which decreased perfusion pressure by 22 +/- 6 mmHg. Authentic 19- and 20-HETE isomers resulted in dose-dependent dilation, as did 18(R)- and 16(R)-HETEs, whereas their enantiomers and 17-HETE isomers were without effect on perfusion pressure. The vasodilator effects of 18(R)- and 16(R)-HETEs, like 20- and 19-HETEs, were inhibited by indomethacin. Furthermore, P-450 HETEs exhibited both regio- and stereoselective inhibition of proximal tubule adenosine triphosphatase (ATPase) activity. The (S) enantiomers of 16- and 17-HETE potently inhibited activity, whereas their (R) isomers and other P-450 HETEs had negligible effects on ATPase activity. The quantity of HETEs released from the kidney, either under basal conditions or when stimulated by ANG II, and their biological profile suggest that subterminal HETEs may participate in renal mechanisms affecting vasomotion and tubular transport.
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PMID:Cytochrome P-450-dependent HETEs: profile of biological activity and stimulation by vasoactive peptides. 889 75

Development of a bioartificial renal tubule with a confluent monolayer of renal epithelial cells supported on a permeable synthetic surface may be the first step to further optimization of renal substitution therapy currently used with hemodialysis or hemofiltration. Madin-Darby canine kidney cells, a permanent renal epithelial cell line, were seeded into the lumen of single hollow fibers. Functional confluence of the cells was demonstrated by the recovery of intraluminally perfused 14C-inulin that averaged >98.9% in the cell lined units vs <7.4% in the control noncell hollow fibers during identical pressure and flow conditions. The baseline absolute fluid transport rate averaged 1.4+/-0.4 microl/30 min. To test the dependency of fluid flux with oncotic and osmotic pressure differences across the bioartificial tubule, albumin was added to the extracapillary space, followed by the addition of ouabain, an inhibitor of Na+K+ adenosine triphosphatase, the enzyme responsible for active transport across the renal epithelium. Addition of albumin resulted in a significant increase in volume transport to 4.5+/-1.0 microl/30 min. Addition of ouabain inhibited transport back to baseline levels of 2.1+/-0.4 microl/30 min. These results are the first demonstration that renal epithelial cells have been grown successfully as a confluent monolayer along a hollow fiber, and exhibit functional transport capabilities. The next steps in constructing a bioartificial renal tubule successfully are to develop a multi-fiber bioreactor with primary renal proximal tubule cells that maintain not only transport properties but also differentiated metabolic and endocrine functions, including glucose and ammonia production, and the conversion of vitamin D3 to a more active derivative. A renal tubule device may add critical renal functional components not currently substituted for, thereby improving the treatment regimens for patients with acute and chronic renal failure.
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PMID:Tissue engineering of a bioartificial renal tubule. 961 48

An acidic milieu is required for sperm maturation and for keeping sperm quiescent during storage in the cauda epididymidis. Previous studies have implicated a Na+/H+ exchanger (NHE) in epididymal acidification together with carbonic anhydrase (CA) and vacuolar proton adenosine triphosphatase (H(+)-ATPase). The present studies were undertaken to discover whether the NHE isoform involved is NHE-3, which is known to mediate Na+ and HCO3- absorption in renal tubules. Using the reverse transcription polymerase chain reaction technique (RT-PCR), Northern blot analysis and in situ hybridization, NHE-3 mRNA was detected mainly in the cauda epididymis and to a lesser extent in other regions of the epididymis. Immunohistochemical studies showed that NHE-3 was present in the apical membranes of the epithelial principal cells and confirmed that its expression is strongest in the cauda region, decreasing towards the more proximal regions. Immunoblotting showed a similar expression pattern. These results demonstrate that NHE-3 is expressed in the rat epididymal duct with strongest expression in its cauda region. These findings are thus consistent with the possibility that NHE-3 in the epididymal duct is involved in luminal Na+ and/or HCO3- absorption, as in the renal proximal tubule, and thereby in the regulation of sperm motility and maturation.
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PMID:An apical membrane Na+/H+ exchanger isoform, NHE-3, is present in the rat epididymal epithelium. 1141 19

Human proximal tubule epithelial cell lines are potentially useful models to elucidate the complex cellular and molecular details of water and electrolyte homeostasis in the kidney. Samples of normal adult human kidney tissue were obtained from surgical specimens, and S1 segments of proximal convoluted tubules were microdissected, placed on collagen-coated culture plate inserts, and cocultured with lethally irradiated 3T3 fibroblasts. Primary cultures of proximal tubule epithelial cells were infected with a replication-defective retroviral construct encoding either wild-type or temperature-sensitive simian virus 40 large T-antigen. Cells forming electrically resistive monolayers were selected and expanded in culture. Three cell lines (HPCT-03-ts, HPCT-05-wt, and HPCT-06-wt) were characterized for proximal tubule phenotype by electron microscopy, electrophysiology, immunofluorescence, Southern hybridization, and reverse transcriptase-polymerase chain reaction. Each of the three formed polarized, resistive epithelial monolayers with apical microvilli, tight junctional complexes, numerous mitochondria, well-developed Golgi complexes, extensive endoplasmic reticulum, convolutions of the basolateral plasma membrane, and a primary cilium. Each exhibited succinate, phosphate, and Na,K- adenosine triphosphatase (ATPase) transport activity, as well as acidic dipeptide- and adenosine triphosphate-regulated mechanisms of ion transport. Transcripts for Na(+)-bicarbonate cotransporter, Na(+)-H(+) exchanger isoform 3, Na,K-ATPase, parathyroid hormone receptor, epidermal growth factor receptor, and vasopressin V2 receptor were identified. Furthermore, immunoreactive sodium phosphate cotransporter type II, vasopressin receptor V1a, and CLIC-1 (NCC27) were also identified. These well-differentiated, transport-competent cell lines demonstrated the growth, immortalization, and differentiation potential of normal, adult, human proximal tubule cells and consequently have wide applicability in cell biology and renal physiology.
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PMID:Growth, immortalization, and differentiation potential of normal adult human proximal tubule cells. 1474 22

It has been documented that angiotensin II (ANG II) (10(-9) M) stimulates proton extrusion via H(+)-adenosine triphosphatase (ATPase) in proximal tubule cells. In the present study, we investigated the signaling pathways involved in the effects of ANG II on H(+)-ATPase activity and on the cytosolic free calcium concentration in immortalized rat proximal tubule cells, a permanent cell line derived from rat proximal tubules. The effects of ANG on pH(i) and [Ca(+2)](i) were assessed by the fluorescent probes, 2',7-bis (2-carboxyethyl)-5(6)-carboxyfluorescein-acetoxy-methyl ester and fluo-4-acetoxy-methyl ester, in the absence of Na(+) to block the Na(+)/H(+) exchanger. In the control situation, the pH recovery rate following intracellular acidification with NH(4)Cl was 0.073+/-0.011 pH units/min (n=12). This recovery was significantly increased with ANG II (10(-9 )M), to 0.12+/-0.015 pH units/min, n=10. This last effect was also followed by a significant increase of Ca(+2) (i), from 99.72+/-1.704 nM (n=21) to 401.23+/-33.91 nM (n=39). The stimulatory effect of ANG II was blocked in the presence of losartan, an angiotensin II subtype 1 (AT(1)) receptor antagonist. H89 [protein kinase A (PKA) inhibitor] plus ANG II had no effect on the pH recovery. Staurosporine [protein kinase C (PKC) inhibitor] impaired the effect of ANG II. Phorbol myristate acetate (PKC activator) mimicked in part the stimulatory effect of ANG II, but reduced Ca(+2) (i). 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (intracellular calcium chelator) alone reduced the pH(i) recovery rate below control levels and impaired the effect of ANG II, in a way similar to that of trimethoxy benzoate (a blocker of Ca(+2) (i) mobilization). We conclude that ANG II regulates rat proximal tubule vacuolar H(+)-ATPase by a PKA-independent mechanism and that PKC and intracellular calcium play a critical role in this regulation.
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PMID:Signaling pathways involved with the stimulatory effect of angiotensin II on vacuolar H+-ATPase in proximal tubule cells. 1668 Apr 84


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