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 in humans is associated with incomplete distal renal tubular acidosis, presenting as the inability to respond appropriately to an acid challenge by excreting less acid. Here, we induced hypothyroidism in rats with methimazole (HYPO) and in one group substituted with l-thyroxine (EU). After 4 wk, acid-base status was similar in both groups. However, after 24 h acid loading with NH(4)Cl HYPO rats displayed a more pronounced metabolic acidosis. The expression of the Na(+)/H(+) exchanger NHE3, the Na(+)-phosphate cotransporter NaPi-IIa, and the B2 subunit of the vacuolar H(+)-ATPase was reduced in the brush-border membrane of the proximal tubule of the HYPO group, paralleled by a lower abundance of the Na(+)/HCO(3)(-) cotransporter NBCe1 and a higher expression of the acid-secretory type A intercalated cell-specific Cl(-)/HCO(3)(-) exchanger AE1. In contrast to control conditions, the expression of NBCe1 was increased in the HYPO group during metabolic acidosis. In addition, net acid excretion was similar in both groups. The relative number of type A intercalated cells was increased in the connecting tubule and cortical collecting duct of the HYPO group during acidosis. Thus thyroid hormones modulate the renal response to an acid challenge and alter the expression of several key acid-base transporters. Mild hypothyroidism is associated only with a very mild defect in renal acid handling, which appears to be mainly located in the proximal tubule and is compensated by the distal nephron.
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PMID:Thyroid hormone deficiency alters expression of acid-base transporters in rat kidney. 1740 79

Vacuolar H(+)-ATPase are multi-subunit containing pumps important for several processes along the nephron such as receptor mediated endocytosis, acidification of intracellular organelles, bicarbonate reabsorption and secretion, and H(+)- extrusion. Mutations in the human a4 (ATP6V0A4) subunit cause distal renal tubular acidosis (dRTA). There are 4 known isoforms of the 'a' subunit (a1-a4). Here we investigated the expression and localization of all four isoforms in mouse kidney. Real-time PCR detected mRNAs encoding all four 'a' isoforms in mouse kidney with a relative abundance in the following order: a4>a2=a1>a3. Immunolocalization demonstrated expression of all 'a' subunits in the proximal tubule and in the intercalated cells of the collecting system. In intercalated cells a1 and a4 isoforms appeared on both the apical and basolateral side and were expressed in all subtypes of intercalated cells. In contrast, a2, and a3 were only found in the apical membrane. a1 and a4 were colocalized in the same cells with AE1 or pendrin, whereas a2 was only found in AE1 positive cells but absent from pendrin expressing intercalated cells. These results suggest that vacuolar H(+)-ATPases containing different 'a' isoforms may serve specific and distinct functions and may help explaining why loss of the a4 isoform causes only dRTA without an apparent defect in the proximal tubule.
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PMID:Differential localization of vacuolar H+-ATPases containing a1, a2, a3, or a4 (ATP6V0A1-4) subunit isoforms along the nephron. 1759 21

In the present study, the effect of potassium depletion on the expression of acid-base transporters in the collecting duct was examined. Toward this end rats were fed a potassium-free diet for 3 weeks. Thereafter, the expression of the basolateral chloride/bicarbonate exchangers AE1 and SLC26A7 and the apical H(+)-ATPase was examined by northern hybridization, immunoblot analysis and immunofluorescence labelling. The mRNA expression of AE1 increased by a robust approximately 500% in the cortex and approximately 70% in the outer medulla, which translated into a huge increase in AE1 protein abundance in the cortex and a moderate increase in the outer medulla in K-depletion. The mRNA expression of SLC26A7 did not change significantly but its protein abundance showed a robust increase in the outer medulla. The expression of SLC26A7 remained undetected in the cortex in K-depleted rats. The post translational increase in SLC26A7 membrane abundance in potassium depletion was recapitulated in vitro using epitope-tagged SLC26A7. H(+)-ATPase displayed enhanced apical plasma membrane immunoreactivity in the OMCD in K-depletion. We suggest that the up-regulation of SLC26A7 and AE1 on the basolateral membrane of A-intercalated cells in the OMCD and CCD, respectively, along with H(+)-ATPase on the apical membrane, contributes to enhanced bicarbonate absorption in the collecting duct in K-depletion.
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PMID:Regulation of the basolateral chloride/base exchangers AE1 and SLC26A7 in the kidney collecting duct in potassium depletion. 1780 57

The preservation of ion balance and pH despite environmental fluctuations is essential for the maintenance of vital cellular functions. While several ion transporters contribute to acid-base regulation in fish, the involvement and expression of key transporters under hypercapnia remain to be established. Here, two members of the HCO(3)(-) transporter family (Na(+)/HCO(3)(-) cotransporter NBC1 and Cl(-)/HCO(3)(-) exchanger AE1) were described for the first time in gills of marine fish. Benthic eelpout Zoarces viviparus were acclimated to 10,000 ppm CO(2). Hypercapnia did not affect whole animal oxygen consumption over a period of 4 days. During a time series of 6 wk NBC1 mRNA levels first decreased by about 40% (8 to 24 h) but finally increased about threefold over control. mRNA expression of AE1 decreased transiently by 50% at day 4 but recovered to control levels only. Reduced mRNA levels were also found for two Na(+)/H(+) exchangers (NHE1A, NHE1B) during the first days (by 50-60% at days 1 and 2), followed by restoration of control levels. This pattern was mirrored in a slight decrease of NHE1 protein contents and its subsequent recovery. In contrast, Na(+)-K(+)-ATPase mRNA and protein contents, as well as maximum activity, rose steadily from the onset of hypercapnia, and reached up to twofold control levels at the end. These results indicate shifting acclimation patterns between short- and long-term CO(2) exposures. Overall, ion gradient-dependent transporter mRNA levels were transiently downregulated in the beginning of the disturbance. Upregulation of NBC1 on long timescales stresses the importance of this transporter in the hypercapnia response of marine teleosts. Long-term rearrangements include Na(+)-K(+)-ATPase at higher densities and capacities, indicating a shift to elevated rates of ion and acid-base regulation under environmental hypercapnia.
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PMID:Acclimation of ion regulatory capacities in gills of marine fish under environmental hypercapnia. 1879 36

The renal collecting system serves the fine-tuning of renal acid-base secretion. Acid-secretory type-A intercalated cells secrete protons via a luminally expressed V-type H(+)-ATPase and generate new bicarbonate released by basolateral chloride/bicarbonate exchangers including the AE1 anion exchanger. Efficient proton secretion depends both on the presence of titratable acids (mainly phosphate) and the concomitant secretion of ammonia being titrated to ammonium. Collecting duct ammonium excretion requires the Rhesus protein RhCG as indicated by recent KO studies. Urinary acid secretion by type-A intercalated cells is strongly regulated by various factors among them acid-base status, angiotensin II and aldosterone, and the Calcium-sensing receptor. Moreover, urinary acidification by H(+)-ATPases is modulated indirectly by the activity of the epithelial sodium channel ENaC. Bicarbonate secretion is achieved by non-type-A intercalated cells characterized by the luminal expression of the chloride/bicarbonate exchanger pendrin. Pendrin activity is driven by H(+)-ATPases and may serve both bicarbonate excretion and chloride reabsorption. The activity and expression of pendrin is regulated by different factors including acid-base status, chloride delivery, and angiotensin II and may play a role in NaCl retention and blood pressure regulation. Finally, the relative abundance of type-A and non-type-A intercalated cells may be tightly regulated. Dysregulation of intercalated cell function or abundance causes various syndromes of distal renal tubular acidosis underlining the importance of these processes for acid-base homeostasis.
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PMID:Regulated acid-base transport in the collecting duct. 1927

Calcineurin inhibitors like FK506 (tacrolimus) are routinely used for immunosuppression following transplantation. Its use is limited by many side effects, including renal tubular acidosis (RTA), mainly of the distal type. In this study, rats were treated with FK506 and at baseline (after 9 days) systemic acid-base status was similar to that in control animals. However, FK506-treated rats given NH(4)Cl in the drinking water for 2 days developed a more severe metabolic acidosis than control animals. Urine pH was more alkaline, but net acid excretion was normal. After 7 days of acid load, all differences related to acid-base homeostasis were equalized in both groups. Protein abundance of type IIa Na-P(i) cotransporter, type 3 Na(+)/H(+) exchanger, and electrogenic Na(+)-bicarbonate cotransporter, and both a4 and B2 subunits of the vacuolar H(+)-ATPase were reduced under baseline conditions, while induction of metabolic acidosis enhanced protein abundance of these transporters in FK506-treated animals. In parallel, protein expression of AE1 was reduced at baseline and increased together with pendrin during NH(4)Cl loading in FK506 rats. Protein abundance of the Na(+)-bicarbonate cotransporter NBCn1 was reduced under baseline conditions but remained downregulated during metabolic acidosis. Morphological analysis revealed an increase in the relative number of non-type A intercalated cells in the connecting tubule and cortical collecting duct at the expense of principal cells. Additionally, subcellular distribution of the a4 subunit of the vacuolar H(+)-ATPase was affected by FK506 with less luminal localization in the connecting tubule and outer medullary collecting duct. These data suggest that FK506 impacts on several major acid-base transport proteins in the kidney, and its use is associated with transient metabolic acidosis and altered expression of key renal acid-base transport proteins.
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PMID:The calcineurin inhibitor FK506 (tacrolimus) is associated with transient metabolic acidosis and altered expression of renal acid-base transport proteins. 1943 19

Kidney proton-secreting A-intercalated cells (A-IC) respond to systemic acidosis by accumulating the vacuolar ATPase (V-ATPase) in their apical membrane and by increasing the length and number of apical microvilli. We show here that the cell-permeant cAMP analog CPT-cAMP, infused in vivo, results in an almost twofold increase in apical V-ATPase accumulation in AE1-positive A-IC within 15 min and that these cells develop an extensive array of apical microvilli compared with controls. In contrast, no significant change in V-ATPase distribution could be detected by immunocytochemistry in B-intercalated cells at the acute time point examined. To show a direct effect of cAMP on A-IC, we prepared cell suspensions from the medulla of transgenic mice expressing EGFP in IC (driven by the B1-subunit promoter of the V-ATPase) and exposed them to cAMP analogs in vitro. Three-dimensional reconstructions of confocal images revealed that cAMP induced a time-dependent growth of apical microvilli, starting within minutes after addition. This effect was blocked by the PKA inhibitor myristoylated PKI. These morphological changes were paralleled by increased cAMP-mediated proton extrusion (pHi recovery) by A-IC in outer medullary collecting ducts measured using the ratiometric probe BCECF. These results, and our prior data showing that the bicarbonate-stimulated soluble adenylyl cyclase (sAC) is highly expressed in kidney intercalated cells, support the idea that cAMP generated either by sAC, or by activation of other signaling pathways, is part of the signal transduction mechanism involved in acid-base sensing and V-ATPase membrane trafficking in kidney intercalated cells.
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PMID:cAMP stimulates apical V-ATPase accumulation, microvillar elongation, and proton extrusion in kidney collecting duct A-intercalated cells. 2005 93

The functional versatility of the distal nephron is mainly due to the large cytological heterogeneity of the segment. Part of Na+ uptake by distal tubules is dependent on Na+/H+ exchanger 2 (NHE2), implicating a role of distal convoluted cells also in acid-base homeostasis. In addition, intercalated (IC) cells expressed in distal convoluted tubules, connecting tubules and collecting ducts are involved in the final regulation of acid-base excretion. IC cells regulate acid-base handling by 2 main transport proteins, a V-type H+-ATPase and a Cl/HCO3- exchanger, localized at different membrane domains. Type A IC cells are characterized by a luminal H+-ATPase in series with a basolateral Cl/HCO3- exchanger, the anion exchanger AE1. Type B IC cells mediate HCO3- secretion through the apical Cl-/HCO3- exchanger pendrin in series with a H+-ATPase at the basolateral membrane. Alternatively, H+/K+-ATPases have also been found in several distal tubule cells, particularly in type A and B IC cells. All of these mechanisms are finely regulated, and mutations of 1 or more proteins ultimately lead to expressive disorders of acid-base balance.
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PMID:Acid-base transport by the renal distal nephron. 2117 Aug 79

The kidney maintains systemic acid-base homeostasis through proximal tubular reclamation of filtered bicarbonate, and excretion of the daily mineral acid load by collecting duct type A intercalated cells. Impairment of either process produces renal tubular acidosis (RTA). This article will provide an overview of familial forms of proximal and distal renal tubular acidosis (pRTA and dRTA). Recessive pRTA with ocular and central nervous system abnormalities is caused by loss-of-function mutations in basolateral membrane Na-HCO3- cotransporter NBCe1/ SLC4A4. Recessive dRTA with deafness is caused by loss-of-function mutations in either of 2 subunits of the vacuolar H+-ATPase (V-ATPase) of intercalated cells; the B1 subunit of the V1 cytoplasmic ATPase complex, and the a4 subunit of the V0 transmembrane pore complex. Dominant and recessive forms of dRTA are also caused by loss-of-function mutations in the basolateral membrane AE1 Cl-/HCO3- exchanger of the type A intercalated cell. The dominant AE1 dRTA mutations are accompanied by mild or asymptomatic erythroid changes, while the erythroid dyscrasias accompanying recessive AE1 dRTA mutations can be mild or severe. Recessive mixed proximal-distal RTA is caused by loss-of-function mutations of the cytoplasmic carbonic anhydrase II. Hyperkalemic RTA accompanied by hypertension (pseudohypoaldosteronism type 2 [PHA2]) is caused by dominant gain-of-function mutations in the kinases WNK1 and WNK4. Hyperkalemic RTA accompanied by volume depletion is caused by loss-of-function mutations in genes encoding the mineralocorticoid receptor or the epithelial Na+ channel (ENaC) subunits. Additional RTA genes identified in knockout mice may lead to identification of additional human RTA genes.
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PMID:Familial renal tubular acidosis. 2117 Aug 90

We report the novel, heterozygous AE1 mutation R730C associated with dominant, overhydrated, cation leak stomatocytosis and well-compensated anemia. Parallel elevations of red blood cell cation leak and ouabain-sensitive Na(+) efflux (pump activity) were apparently unaccompanied by increased erythroid cation channel-like activity, and defined ouabain-insensitive Na(+) efflux pathways of nystatin-treated cells were reduced. Epitope-tagged AE1 R730C at the Xenopus laevis oocyte surface exhibited severely reduced Cl(-) transport insensitive to rescue by glycophorin A (GPA) coexpression or by methanethiosulfonate (MTS) treatment. AE1 mutant R730K preserved Cl(-) transport activity, but R730 substitution with I, E, or H inactivated Cl(-) transport. AE1 R730C expression substantially increased endogenous oocyte Na(+)-K(+)-ATPase-mediated (86)Rb(+) influx, but ouabain-insensitive flux was minimally increased and GPA-insensitive. The reduced AE1 R730C-mediated sulfate influx did not exhibit the wild-type pattern of stimulation by acidic extracellular pH (pH(o)) and, unexpectedly, was partially rescued by exposure to sodium 2-sulfonatoethyl methanethiosulfonate (MTSES) but not to 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA) or 2-(trimethylammonium)ethyl methanethiosulfonate bromide (MTSET). AE1 R730E correspondingly exhibited acid pH(o)-stimulated sulfate uptake at rates exceeding those of wild-type AE1 and AE1 R730K, whereas mutants R730I and R730H were inactive and pH(o) insensitive. MTSES-treated oocytes expressing AE1 R730C and untreated oocytes expressing AE1 R730E also exhibited unprecedented stimulation of Cl(-) influx by acid pH(o). Thus recombinant cation-leak stomatocytosis mutant AE1 R730C exhibits severely reduced anion transport unaccompanied by increased Rb(+) and Li(+) influxes. Selective rescue of acid pH(o)-stimulated sulfate uptake and conferral of acid pH(o)-stimulated Cl(-) influx, by AE1 R730E and MTSES-treated R730C, define residue R730 as critical to selectivity and regulation of anion transport by AE1.
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PMID:Functional characterization and modified rescue of novel AE1 mutation R730C associated with overhydrated cation leak stomatocytosis. 2120 59


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