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)

Hypothyroidism is associated with significant abnormalities in the renal handling of salt and water. To address the involvement of tubular transport proteins in these abnormalities, rats were rendered pharmacologically hypothyroid and the abundance of major tubular transport proteins was assessed by immunoblot and immunohistochemistry. Hypothyroidism resulted in a marked reduction in kidney size and creatinine clearance along with decreased or unchanged total kidney abundance of the transport proteins. Whereas the proximal tubular type 3 Na/H exchanger (NHE3) and type 2 Na-phosphate cotransporter (NaPi2) stood out by their disproportionately reduced abundance, the bumetanide-sensitive type 2 Na-K-2Cl cotransporter (NKCC2) and aquaporin-2 (AQP2) were unaltered in their total kidney abundance despite a markedly lower kidney mass. The latter proteins in fact showed enhanced immunostaining. Decreased NHE3 and NaPi2 expression was most likely due to a combination of triiodo-l-thyronine (T(3)) deficiency along with a reduced glomerular filtration rate. The increased abundance of NKCC2 and AQP2 may have been caused by an increased action of vasopressin since urinary excretion of this hormone was elevated. On the other hand, the thiazide-sensitive Na-Cl cotransporter; the alpha-, beta-, and gamma-subunits of the amiloride-sensitive epithelial Na channel; and the alpha(1)-subunit of Na-K-ATPase showed a moderate decrease in total kidney abundance that was largely proportional to the smaller kidney mass. Although the observed expression of transporters was associated with a balanced renal sodium handling, altered transporter abundance may become functionally relevant if the hypothyroid kidney is challenged by an additional destabilization of the milieu interieur that has previously been shown to result in an inadequate natriuresis and clinical symptoms.
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PMID:Renal expression of sodium transporters and aquaporin-2 in hypothyroid rats. 1256 81

Hypothyroidism is associated with impaired urinary concentrating ability in humans and animals. The purpose of this study was to examine protein expression of renal sodium chloride and urea transporters and aquaporins in hypothyroid rats (HT) with diminished urinary concentration as compared with euthyroid controls (CTL) and hypothyroid rats replaced with L-thyroxine (HT+T). Hypothyroidism was induced by aminotriazole administration. Body weight, water intake, urine output, solute and urea excretion, serum and urine osmolality, serum creatinine, 24-h creatinine clearance, and fractional excretion of sodium were comparable among the three groups. However, with 36 h of water deprivation, HT rats demonstrated significantly greater urine flow rates and decreased urine and medullary osmolality as compared with CTL and HT+T rats at comparable plasma vasopressin concentrations. Western blot analyses revealed decreased renal protein abundance of transporters, including Na-K-2Cl, Na-K-ATPase, and NHE3, in HT rats as compared with CTL and HT+T rats. Protein abundance of renal AQP1 and urea transporters UTA(1) and UTA(2) did not differ significantly among study groups. There was however a significant decrease in protein abundance of AQP2, AQP3, and AQP4 in HT rats as compared with CTL and HT+T rats. These findings demonstrate a decrease in the medullary osmotic gradient secondary to impaired countercurrent multiplication and downregulation of aquaporins 2, 3, and 4 as contributors to the urinary concentrating defect in the hypothyroid rat.
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PMID:Urinary concentrating defect in hypothyroid rats: role of sodium, potassium, 2-chloride co-transporter, and aquaporins. 1259 91

Proximal solute and fluid absorption is greatly reduced in mice in which the gene encoding the Na/H exchanger isoform 3 has been ablated (NHE3-/-). To obtain information on the intracellular functional consequences of such selective NHE3 deficiency, Na, Cl and K concentrations and cell Rb uptake were measured using electron microprobe analysis after a 30-s infusion of Rb (an index of basolateral Na/K-ATPase activity) in proximal convoluted tubule (PCT) cells of NHE3-/- and wild-type (NHE3+/+) mice. In addition, the relative abundance of the alpha1-subunit of the Na/K-ATPase in the outer cortex was determined by Western blot analysis. PCT cell Na concentration in NHE3-/- mice was slightly but significantly lower than in NHE3+/+ [13.1+/-0.6 ( n=64) vs. 14.9+/-0.6 ( n=62) mmol/kg wet wt.; means +/-SEM]. The lower intracellular Na concentration was associated with significantly reduced Rb uptake rates [9.7+/-0.6 ( n=59) vs. 14.8+/-0.8 ( n=50) mmol/kg wet wt./30 s], but the abundance of the alpha1-subunit of the Na/K-ATPase was not different between NHE3-/- and NHE3+/+ mice. Intracellular Cl concentration was higher (14.2+/-0.4 vs. 12.8+/-0.4 mmol/kg wet wt.) and K concentration unchanged (122.7+/-2.7 vs. 121.6+/-2.5 mmol/kg wet wt.) in PCT cells in NHE3-/- compared with NHE3+/+ mice. These findings suggest that the elimination of apical NHE3 in PCT cells of NHE3-/- mice reduces apical Na entry and, due to lower cell Na concentrations, Na/K-ATPase activity. The observed changes in intracellular Na concentration did not affect the expression of Na/K-ATPase in the renal cortex of NHE3-/- mice. There were no significant changes of cell Na concentration and Rb uptake in distal convoluted tubule, connecting tubule, principal and intercalated cells.
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PMID:Intracellular Na concentration and Rb uptake in proximal convoluted tubule cells and abundance of Na/K-ATPase alpha1-subunit in NHE3-/- mice. 1269 Apr 68

An acute increase in blood pressure provokes a rapid decrease in proximal tubule salt and water reabsorption that is central to tubuloglomerular feedback regulation of renal blood flow and glomerular filtration rate and contributes to pressure natriuresis. The molecular mechanisms responsible for this critical homeostatic adjustment were studied. When blood pressure is acutely elevated, apical proximal tubule NHE3 are rapidly redistributed out of the microvilli to intermicrovillar clefts and then endosomal pools, and Na,K-ATPase activity is suppressed. Depressing apical Na(+) entry without hypertension is not sufficient to decrease Na,K-ATPase activity, and depressing Na,K-ATPase activity alone is not sufficient to decrease proximal tubule Na(+) and water reabsorption; thus, it appears that coordinated decreases in both NHE3 surface distribution and Na,K-ATPase activity may be important for the response to acute hypertension. Clamping plasma angiotensin II levels blunts the retraction of NHE3 from the cell surface to endosomal pools. The increased volume flow of salt and water to the loop of Henle stimulates Na,K-ATPase activity in this region and provides evidence for a downstream shift in sodium transport during acute hypertension. These same responses in the proximal tubule and loop develop and persist in the spontaneously hypertensive rat. These studies demonstrate that sodium transporters along the nephron are very dynamic, responding quickly to normal fluctuations of blood pressure, and are key to generating the macula densa tubuloglomerular feedback signal and for accommodating increased volume flow through the loop of Henle.
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PMID:Mechanisms of pressure natriuresis: how blood pressure regulates renal sodium transport. 1276 17

Urinary tract obstruction impairs urinary concentrating capacity and reabsorption of sodium. To clarify the molecular mechanisms of these defects, expression levels of renal sodium transporters were examined in rats with 24-h bilateral ureteral obstruction (BUO) or at day 3 or 14 after release of BUO (BUO-R). BUO resulted in downregulation of type 3 Na+/H+ exchanger (NHE3) to 41 +/- 14%, type 2 Na-Pi cotransporter (NaPi-2) to 26 +/- 6%, Na-K-ATPase to 67 +/- 8%, type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) to 20 +/- 7%, and thiazide-sensitive cotransporter (TSC) to 37 +/- 9%. Immunocytochemistry confirmed downregulation of NHE3, NaPi-2, Na-K-ATPase, BSC-1, and TSC. Consistent with this downregulation, BUO-R was associated with polyuria, reduced urinary osmolality, and increased urinary sodium and phosphate excretion. BUO-R for 3 days caused a persistant downregulation of NHE3 to 53 +/- 10%, NaPi-2 to 57 +/- 9%, Na-K-ATPase to 62 +/- 8%, BSC-1 to 50 +/- 12%, and TSC to 56 +/- 16%, which was associated with a marked reduction in the net renal reabsorption of sodium (616 +/- 54 vs. 944 +/- 24 micromol x min-1 x kg-1; P < 0.05) and phosphate (6.3 +/- 0.9 vs. 13.1 +/- 0.4 micromol x min-1. kg-1; P < 0.05) demonstrating a defect in renal sodium and phosphate reabsorption capacity. Moreover, downregulation of Na-K-ATPase and TSC persisted in BUO-R for 14 days, whereas NHE3, NaPi-2, and BSC-1 were normalized to control levels. In conclusion, downregulation of renal Na transporters in rats with BUO and release of BUO are likely to contribute to the associated urinary concentrating defect, increased urinary sodium excretion, and postobstructive polyuria.
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PMID:Altered expression of major renal Na transporters in rats with bilateral ureteral obstruction and release of obstruction. 1286 55

The present study investigated sodium balance and renal tubular function in cirrhotic rats with chronic blockade of the nitric oxide (NO) system. Rats were treated with the nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) starting on the day of common bile duct ligation (CBL). Three weeks of daily sodium balance studies showed that CBL rats developed sodium retention compared with sham-operated rats and that l-NAME treatment dose dependently deteriorated cumulative sodium balance by reducing urinary sodium excretion. Five weeks after CBL, renal clearance studies were performed, followed by Western blotting of the electroneutral type 3 sodium/proton exchanger (NHE3) and the Na-K-ATPase present in proximal tubules. Untreated CBL rats showed a decreased proximal reabsorption with a concomitant reduction of NHE3 and Na-K-ATPase levels, indicating that tubular segments distal to the proximal tubules were responsible for the increased sodium reabsorption. l-NAME-treated CBL rats showed an increased proximal reabsorption measured by the lithium clearance method and showed a marked increase in NHE3 and Na-K-ATPase protein levels. Our results show that chronic l-NAME treatment exacerbates the sodium retention found in CBL rats by a significant increase in proximal tubular reabsorption.
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PMID:Chronic nitric oxide synthase inhibition exacerbates renal dysfunction in cirrhotic rats. 1458 32

Mammalian cells regulate their cytosolic pH through a variety of proton extruding and bicarbonate loading mechanisms. The human embryonic kidney cell line HEK 293 is thought to show some characteristics of proximal tubule cells. The present study was performed to investigate the activity of proton extruding mechanisms (i.e. Na(+)/H(+) exchange and/or V-H(+)-ATPases) and the influence of intracellular pH (pH(i)) on the activation of these transport processes. At resting pH(i) (7.4) and in the absence of bicarbonate, removal of extracellular Na(+) did not alter pH(i) Intracellular acidification (pH(i) approximately 6.2) after a NH(4)Cl prepulse (20 mM) followed by exposure to a Na(+) free bath solution led to a slow pH(i) recovery (with a delay of 5 min), which was inhibited by the specific vacuolar H(+)-ATPase inhibitor bafilomyocin. There was no Na(+)-dependent pH(i) recovery upon exposure to Na(+) after a short intracellular acidification (less than 5 min). However, when the intracellular acidification phase was extended, the activation of a Na(+)-dependent pH(i) recovery was seen. This Na(+)-dependent pH(i) recovery was inhibited by 30 microM EIPA but not by 2 microM EIPA or less, suggesting the involvement of NHE3. Western blot analysis confirmed the presence of NHE3 protein in HEK 293 cells. Disruption of the microtubular network by colchicine (20 microM) did not significantly inhibit the rate of Na(+)-independent or dependent pH(i) recovery indicating that activation of both H(+)-ATPase, and the NHE were not due to stimulated trafficking of the transport proteins or some activators to the membrane. We conclude that a) the plasma membrane of HEK293 cells contains both, NHE and H(+)-ATPase and b) both H(+) extrusion systems are inactive at neutral pH(i), c) a decrease of cytosolic pH to 6.5 activates both transport proteins in a slow, time-dependent manner.
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PMID:Intracellular pH activates membrane-bound Na(+)/H(+) exchanger and vacuolar H(+)-ATPase in human embryonic kidney (HEK) cells. 1458 69

Synthetic agonists of the peroxisomal proliferator-activated receptor subtype gamma (PPAR-gamma) are highly beneficial in the treatment of type II diabetes. However, they are also associated with fluid retention and edema, potentially serious side effects of unknown origin. These studies were designed to test the hypothesis that rosiglitazone (RGZ, PPAR-gamma agonist) may activate sodium- and water-reabsorptive processes in the kidney, possibly in response to a drop in mean arterial blood pressure (MAP), as well as directly through PPAR-gamma. Targeted proteomics of the major renal sodium and water transporters and channel proteins was used to identify potentially regulated sites of renal sodium and water reabsorption. RGZ (47 or 94 mg/kg diet) was fed to male, Sprague-Dawley rats (approximately 270g) for 3 days. MAP, measured by radiotelemetry, was decreased significantly in rats fed either level of RGZ, relative to control rats. Delta MAP from baseline was -3.2 +/- 1.2 mm Hg in rats fed high-dose RGZ versus + 3.4 +/- 0.8 for rats fed control diet. RGZ did not affect feed or water intake, but rats treated with high-dose RGZ had decreased urine volume (by 22%), sodium excretion (44%), kidney weight (9%), and creatinine clearance (35%). RGZ increased whole kidney protein abundance of the alpha-1 subunit of Na-K-ATPase, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), the sodium hydrogen exchanger (NHE3), the aquaporins 2 and 3, and endothelial nitric-oxide synthase. We conclude that both increases in renal tubule transporter abundance and a decrease in glomerular filtration rate likely contribute to the RGZ-induced sodium retention.
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PMID:Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lowers blood pressure in normal rats. 1459 89

The purpose of this study was to evaluate whether the natriuresis and polyuria seen in parathyroid hormone (PTH)-induced hypercalcemia are associated with dysregulation of renal Na transporters. Rats were infused with three different doses of human PTH [PTH (1-34); 7.5, 10, and 15 microg.kg(-1).day(-1) s.c.] or vehicle for 48 h using osmotic minipumps. The rats treated with PTH developed significant hypercalcemia (plasma total calcium levels: 2.71 +/- 0.03, 2.77 +/- 0.02, and 3.42 +/- 0.06 mmol/l, respectively, P < 0.05 compared with corresponding controls). The rats with severe hypercalcemia induced by high-dose PTH developed a decreased glomerular filtration rate (GFR), increased urine output, reduced urinary osmolality, increased urinary Na excretion, and fractional excretion of Na. This was associated with downregulation (calculated as a fraction of control levels) of whole kidney expression of type 2 Na-P(i) cotransporter (NaPi-2; 16 +/- 6%), type 3 Na/H exchanger (NHE3; 42 +/- 7%), Na-K-ATPase (55 +/- 2%), and bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1; 25 +/- 4%). In contrast, an upregulation of the Ca(2+)-sensing receptor (CaR) was observed. Rats treated with moderate-dose PTH exhibited unchanged GFR but decreased urinary concentration. The whole kidney expression of NHE3 (52 +/- 8%) and NaPi-2 (26 +/- 5%) was persistently decreased, whereas BSC-1 and Na-K-ATPase protein levels were not altered. CaR expression was also increased. Moreover, rats treated with low-dose PTH showed very mild hypercalcemia but unchanged GFR, normal urinary concentration, and unchanged expression of Na transporters and CaR. In conclusion, the reduced expression of major renal Na transporters is likely to play a role in the increased urinary Na excretion and decreased urinary concentration in rats with PTH-induced hypercalcemia. Moreover, the increase in the CaR in the thick ascending limb (TAL) may indicate a potential role of the CaR in inhibiting Na transport in the TAL.
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PMID:Reduced expression of renal Na+ transporters in rats with PTH-induced hypercalcemia. 1462 99

Current understanding of chloride cells (CCs) is briefly reviewed with emphasis on molecular aspects of their channels, transporters and regulators. Seawater-type and freshwater-type CCs have been identified based on their shape, location and response to different ionic conditions. Among the freshwater-type CCs, subpopulations are emerging that are implicated in the uptake of Na(+), Cl(-) and Ca(2+), respectively, and can be distinguished by their shape of apical crypt and affinity for lectins. The major function of the seawater CC is transcellular secretion of Cl(-), which is accomplished by four major channels and transporters: (1). CFTR Cl(-) channel, (2). Na(+),K(+)-ATPase, (3). Na(+)/K(+)/2Cl(-) cotransporter and (4). a K(+) channel. The first three components have been cloned and characterized, but concerning the K(+) channel that is essential for the continued generation of the driving force by Na(+),K(+)-ATPase, only one candidate is identified. Although controversial, freshwater CCs seem to perform the uptake of Na(+), Cl(-) and Ca(2+) in a manner analogous to but slightly different from that seen in the absorptive epithelia of mammalian kidney and intestine since freshwater CCs face larger concentration gradients than ordinary epithelial cells. The components involved in these processes are beginning to be cloned, but their CC localization remains to be established definitively. The most important yet controversial issue is the mechanism of Na(+) uptake. Two models have been postulated: (i). the original one involves amiloride-sensitive electroneutral Na(+)/H(+) exchanger (NHE) with the driving force generated by Na(+),K(+)-ATPase and carbonic anhydrase (CA) and (ii). the current model suggests that Na(+) uptake occurs through an amiloride-sensitive epithelial sodium channel (ENaC) electrogenically coupled to H(+)-ATPase. While fish ENaC remains to be identified by molecular cloning and database mining, fish NHE has been cloned and shown to be highly expressed on the apical membrane of CCs, reviving the original model. The CC is also involved in acid-base regulation. Analysis using Osorezan dace (Tribolodon hakonensis) living in a pH 3.5 lake demonstrated marked inductions of Na(+),K(+)-ATPase, CA-II, NHE3, Na(+)/HCO(3)(-) cotransporter-1 and aquaporin-3 in the CCs on acidification, leading to a working hypothesis for the mechanism of Na(+) retention and acid-base regulation.
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PMID:Molecular biology of major components of chloride cells. 1466 88


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