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)

A very early event in the toxicity of pentachlorobutadienyl-L-cysteine (PCBC) to rabbit renal proximal tubules is uncoupling of oxidative phosphorylation (R.G. Schnellmann, E. A. Lock, and L. J. Mandel (1986), Toxicologist 6, 176; (1987), Toxicol. Appl. Pharmacol. 90, 521). The mechanism of PCBC uncoupling of mitochondrial oxidative phosphorylation has been investigated using isolated rabbit renal cortical mitochondria (RCM). PCBC increased state 4 respiration of RCM respiring on pyruvate/malate or succinate in a concentration (10-100 microM)- and time (1-5 min)-dependent manner. PCBC also increased state 4 respiration in the presence of oligomycin, an inhibitor of F0F1-ATPase. The effect of PCBC on mitochondrial proton permeability was determined by measuring passive mitochondrial swelling. After a 2-min exposure to PCBC, RCM swelled when placed in NH4Cl or NaCl, but not KCl or sucrose. The protonophore carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP) (1 microM) produced similar effects. After 5 min, RCM swelled when placed in NH4Cl, NaCl, or KCl, but not in sucrose. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, blocked the effects of PCBC on respiration, indicating that PCBC can be metabolized by RCM to produce RCM toxicity. These results show that PCBC initially uncouples oxidative phosphorylation by dissipating the proton gradient. Subsequently, additional ion permeabilities occur. These results are in complete agreement with previous observations in rabbit renal proximal tubule suspensions.
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PMID:Pentachlorobutadienyl-L-cysteine uncouples oxidative phosphorylation by dissipating the proton gradient. 255 Oct 76

A viable suspension of proximal tubules that had sustained an in vivo ischemic injury was harvested, and cellular integrity and viability were determined. The histopathological appearance of this preparation has characteristic features of an ischemic injury and ATP levels were comparable to those observed with nuclear magnetic resonance spectroscopy in vivo. Sprague-Dawley rats were subjected to 45 min of bilateral renal artery ischemia and the kidneys were allowed to reperfuse for either 15 min, 2 h, or 24 h before the harvest of the proximal tubule suspension. There was a decrease in base-line oxygen consumption from 34 +/- 0.8 nmol O2.min-1.mg protein-1 to 22 +/- 0.6 at 15 min of reflow. This decline in oxygen consumption persisted during the first 2 h of reflow and returned to control levels by 24 h. Residual respiration in the presence of ouabain was similar at all reflow intervals suggesting that the decrease in basal O2 consumption was related to decreased Na+-K+-ATPase in situ. In contrast, there was no significant difference in Na+-K+-ATPase activity when determined chemically under Vmax conditions in all experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolic alterations in proximal tubule suspensions obtained from ischemic kidneys. 255 Nov 86

In proximal tubular cells ischemia is known to result in the redistribution of apical and basolateral domain-specific lipids and proteins into the alternate surface membrane domain. Since tight junctions are required for the maintenance of surface membrane polarity, the effect of ischemia on tight junction functional integrity was investigated. In vivo microperfusion of early loops of proximal tubules with ruthenium red (0.2%) in glutaraldehyde (2%) was used to gain selective access to and outline the apical surface membrane. Under control situations ruthenium red penetrated less than 10% of the tight junctions. After 5, 15, and 30 min of ischemia, however, there was a successive stepwise increase in tight junction penetration by ruthenium red to 29, 50, and 62%, respectively. This was associated with the rapid duration-dependent redistribution of basolateral membrane domain-specific lipids and NaK-ATPase into the apical membrane domain. Taken together, these data indicate that during ischemia proximal tubule tight junctions open, which in turn leads to the lateral intramembranous diffusion of membrane components into the alternate surface membrane domain.
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PMID:Ischemia-induced loss of epithelial polarity. Role of the tight junction. 255 26

Endothelin, a potent vasoconstrictor released by vascular endothelial cells, can induce natriuresis in vivo. These studies examined the regulation of Na+ transport by endothelin in suspensions of rabbit proximal tubule (PT) and inner medullary collecting duct (IMCD) cells. Endothelin reduced oxygen consumption (QO2) by 18 +/- 1% in IMCD cells but did not alter QO2 in PT cells. In IMCD cells, endothelin inhibited QO2 half maximally at approximately 5 x 10(-12) M. Several lines of evidence indicate that endothelin reduces QO2 by inhibiting the Na(+)-K(+)-ATPase. 1) Endothelin gave no further inhibition of QO2 after ouabain and blunted the stimulatory effect of amphotericin B on QO2 (+29 +/- 4% in absence of endothelin, 0 +/- 5% in presence of endothelin; n = 6 preparations, P less than 0.001). 2) Endothelin inhibited ouabain-sensitive 86Rb+ uptake by 46.6 +/- 8.6% at 10 s and by 35.4 +/- 5.3% at 30 s without altering uptake at 60 min. 3) Addition of endothelin to IMCD cells induced a net K+ efflux with an initial rate of 32.2 +/- 4.8 nmol.min-1.mg protein-1, consistent with inhibition of the Na(+)-K(+)-ATPase. In contrast to the response observed in intact cells, in permeabilized IMCD cells endothelin did not inhibit ouabain-sensitive ATPase. Several observations indicated that prostaglandin E2 (PGE2) mediates endothelin inhibition of Na(+)-K(+)-ATPase activity. 1) The response to endothelin was blocked by ibuprofen in assays of QO2, net K+ flux, and 86Rb+ uptake. 2) Endothelin and PGE2 gave equivalent, nonadditive inhibition of ouabain-sensitive 86Rb+ uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelin, a peptide inhibitor of Na(+)-K(+)-ATPase in intact renaltubular epithelial cells. 255 68

There are several lines of indirect evidence suggesting that the renal tubule cells have not yet reached terminal differentiation at birth. Methods used in cell biology can now be applied to study renal ontogeny. This review describes how primary cultures of proximal tubule cells from rats can be used to investigate developmental changes in Na permeability and Na-K-ATPase-mediated transport.
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PMID:Studies of terminal differentiation of electrolyte transport in the renal proximal tubule using short-term primary cultures. 256 16

Dopamine, like other neurotransmitters, exerts its biological effects by occupation of specific receptor subtypes. The dopamine receptors in the central nervous system and certain endocrine organs are classified into the D1/D2 subtypes. Outside the central nervous system, the dopamine receptors are classified into the DA1/DA2 subtypes. The D1/D2 and DA1/DA2 receptor have marked similarities and some differences, the most notable of which is the lower affinity of the DA dopamine compared with the D dopamine receptor. DA1 receptor activation increases renal blood flow (RBF); stimulation of DA1 and DA2 receptors may also increase glomerular filtration rate (GFR). DA1 agonists inhibit fluid and electrolyte transport indirectly via hemodynamic mechanisms and directly by occupation of DA1 receptors in specific nephron segments. In the proximal tubule, DA1 agonists simulate adenylate cyclase and inhibit Na+-H+ antiport activity. They also increase phospholipase C and inhibit Na+-K+-ATPase activity (presumably as a consequence of protein kinase C activation). The latter effects may be facilitated by DA2 agonists. In cortical collecting ducts, dopamine antagonizes the effects of mineralocorticoids and the hydrosomotic effect of antidiuretic hormone. It has also been suggested that DA1 may also decrease sodium transport by influencing other hormones, such as atrial natriuretic peptide. Studies of dopamine in the young are complicated because of the propensity for dopamine to stimulate alpha-adrenoceptors. Dopamine alone may actually decrease RBF in the perinatal period. In some animals, the renal vasodilatory and natriuretic effects of dopamine increase with age. Renal tubular DA1-stimulated adenylate cyclase activity increases, whereas renal tubular DA1 receptors decrease with age. Renal DA2 receptor density is greater in the fetus; after birth renal DA2 receptors do not change. Endogenous dopamine may regulate sodium excretion in the young differently than in the adult. In the adult, sodium surfeit is associated with an increase in urinary dopamine; the opposite occurs in the young. A decrease in dopamine production or blockade of dopamine receptors results in an antinatriuresis in the adult; dopamine blockade in the young results in a natriuresis. It remains to be determined whether these age-related differences in dopamine effects are due to changes in receptor DA subtype density, second messengers, and/or interaction with other receptors.
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PMID:The dopamine receptor in adult and maturing kidney. 257 2

The reabsorption of amino acids by the proximal tubule is remarkably efficient. Current evidence indicates that this process occurs by Na+-amino acid cotransport or symport. The energy for amino acid entry is derived from the chemical and voltage gradient for Na+ entry across the apical surface of the renal cell maintained by pumping Na+ out of the cell by Na+-K+-adenosine triphosphatase (ATPase) activity at the basolateral membrane. We chose the beta-amino acid taurine to study the anionic requirements as well as voltage- and pH-dependence of Na+-taurine symport into rat proximal tubule brush border membrane vesicles. Maximal uptake was found when Cl- or Br- were the anions. The addition of various ionophores (amiloride, carbonyl cyanide-n chlorophenyl-hydrazone, and valinomycin) under pH-equilibrated conditions did not change taurine entry into the vesicle. Hill equation analysis of the initial rate of taurine uptake into vesicles indicates that transport operates by means of a 2 Na+:1 Cl-:1 taurine-carrier complex. Because taurine is a zwitterion, this complex has a net positive charge. Its entry into the vesicle is favored by the imposition of an outwardly directed K+ gradient in the presence of valinomycin. The movement of a quaternary complex of this type across the apical surface of the proximal tubular cell would assure that the movement of both Cl- and the amino acid is energized by the Na+ gradient. Because most amino acids are zwitterions at physiologic pH this complex would be positively charged, favoring entry into the voltage negative renal cell interior.
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PMID:Ionic requirements for amino acid transport. 280 2

The mechanisms by which uranyl nitrate (UN) is toxic to the proximal tubule are incompletely understood. To define these further we studied potassium (K+) transport and oxygen consumption (QO2) in rabbit proximal tubule suspensions in vitro immediately after exposure to UN using extracellular O2- and K+-sensitive electrodes. UN caused a cumulative dose-dependent inhibition of proximal tubule QO2, with a threshold concentration of 5 x 10(-5) M. Kinetic analysis suggested two patterns of cell injury: a higher affinity inhibition of QO2 with a Ki of 5 x 10(-4) M, and a lower affinity inhibition of QO2 with a Ki of 10 mM. QO2 was studied in detail in the presence of these Ki concentrations of UN to define the initial cellular events. The results indicated that different cellular processes displayed different sensitivities to UN. At submillimolar concentrations UN caused progressive selective inhibition of ouabain-insensitive QO2 (15% inhibition at 2 minutes). Ouabain-sensitive QO2 and nystatin-stimulated QO2 were not affected, suggesting that Na+,K+-ATPase activity and its coupling to mitochondrial ATP synthesis were intact. Direct measurement of proximal tubule net K+ flux confirmed that Na+,K+-ATPase activity was unchanged. Similarly, UN did not inhibit basal (state 4) or ADP-stimulated (state 3) mitochondrial QO2 in digitonin-permeabilized tubules, confirming that the mitochondria were intact. In contrast, higher concentrations of UN (greater than or equal to 1 mM) caused rapid inhibition of QO2 and net K+ efflux, due to inhibition of Na+,K+-ATPase activity and mitochondrial injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early effects of uranyl nitrate on respiration and K+ transport in rabbit proximal tubule. 281 Oct 55

We have recently demonstrated that dopamine (DA) inhibits Na,K-ATPase in single proximal tubule (PCT) segments dissected from previously collagenase perfused rat kidney. The aim of the present study was to ascertain whether this effect was directly mediated by DA or if DA was the precursor of an inhibitor. When PCT segments were incubated with L-DOPA, Na,K-ATPase was significantly lower than in vehicle incubated tubules. Inhibition of dopa decarboxylase abolished the effect of L-DOPA on Na,K-ATPase activity. The metabolites of DA, 3, 4-dihydroxphenyl acetic acid (DPAC) and homovanillic acid (HVA) both inhibited Na,K-ATPase activity in doses higher than 10(-6) M. Both HVA and DPAC 10(-4) M caused approximately 35% inhibition. Dopamine inhibited Na,K-ATPase activity even in a dose as low as 10(-7) M. Maximal inhibition (greater than 60%) was found with DA-5 M. Na,K-ATPase activity was significantly lower in tubules exposed to DA 10(-4) and 10(-5) M than in tubules exposed to DPAC or HVA 10(-4) and 10(-5) M. Dopamine produced in proximal tubule cells from L-DOPA, is an active inhibitor of the Na,K-pump in these cells. The DA metabolites DPAC and HVA are less potent Na,K-pump-inhibitors.
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PMID:Effect of L-DOPA, dopamine, dihydroxyphenyl acetic acid and homovanillic acid on Na,K-ATPase activity in rat proximal tubule segments. 282 Jan 98

Prolonged cadmium exposure has been associated with proteinuria, calcuria and loss of calcium from bones in humans. Previous studies have shown that kidney uptake of cadmium in vivo results from proximal tubule absorption of the circulating cadmium metallothionein complex (CdMT), and intracellular release of the Cd2+ ion prior to induction of renal metallothionein. Parenteral administration of CdMT has been found to selectively damage the proximal tubule cell lysosome system with development of a tubular proteinuria pattern similar to that observed under chronic exposure conditions. The present studies also demonstrate a concomitant calcuria but no changes in the excretion of other electrolytes or glucose using this model. These marked changes in renal calcium metabolism occurred in the absence of mitochondrial damage, changes in total, Na/K or Mg-stimulated ATPase activities, renal ATP levels, membrane 45Ca2+ transport or overt tubule cell necrosis during an 8 hour period following CdMT injection. Proteinuria and calcuria were prevented by prior zinc induction of the renal MT pool. Data from these studies indicate that renal proximal tubule cell uptake and degradation of the circulating CdMT complex produces both a marked proteinuria and calcuria. The calcuria does not appear to stem from changes in renal energy metabolism or membrane transport of this element but is probably a secondary result of calcium binding to excreted proteins which are increased in urine to a similar extent. The studies also suggest that zinc status and maintenance of the renal ZnMT pool may play an important role in regulating cadmium-induced renal proteinuria and calcuria by preventing Cd2+ perturbation of the proximal tubule cell lysosome system.
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PMID:Mechanism of cadmium-metallothionein-induced nephrotoxicity: relationship to altered renal calcium metabolism. 282 68


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