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)

The kidney plays a major role in maintaining and controlling systemic acid-base homeostasis by reabsorbing bicarbonate and secreting protons and acid-equivalents, respectively. During postnatal kidney development and adaptation to changing diets, plasma bicarbonate levels are increasing, the capacity for urinary acidification maturates, and the final morphology and distribution of intercalated cells is achieved. In adult kidney, at least two types of intercalated cells (IC) are found along the collecting duct characterised either by the expression of AE1 (type A IC) or pendrin (non-type A IC) where non-type A IC are found only in the convoluted distal tubule, connecting tubule and cortical collecting duct. Here we investigated in mouse kidney the relative mRNA abundance, protein expression levels and distribution of several proteins involved in renal acid-base transport, namely, the Na(+)/HCO(3)(-) cotransporter NBC1 (SLC4A4), the Na(+)/H(+)-exchanger NHE3 (SLC9A3), two subunits of the vacuolar H(+)-ATPase [ATP6V0A4 (a4), ATP6V1B1 (B1)], the Cl(-)/HCO(3)(-) exchangers AE1 (SLC4A1) and pendrin (SLC26A4). Relative mRNA abundance of all transport proteins was lowest at day 3 after birth and increased thereafter in parallel with protein levels. The numbers of type A and non-type A IC in the cortical collecting duct (CCD) increased from day 3 to days 18 and 24, whereas the number of IC in the CCD with apical staining for the vacuolar H(+)-ATPase subunits a4 and B1 decreased from day 3 to days 18 and 24, respectively. In addition, cells with characteristics of non-type A IC (pendrin expression, basolateral expression of vacuolar H(+)-ATPase subunits) were found in the inner and outer medulla 3 days after birth but were absent from the medulla of 24-day-old mice. Taken together, these results demonstrate massive changes in mRNA and protein expression levels of several acid-base transporters during postnatal kidney maturation and also show changes in intercalated cell phenotype in the medulla during these processes.
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PMID:Postnatal expression of transport proteins involved in acid-base transport in mouse kidney. 1475 80

This study compared the expression of enzymes and transport and channel proteins involved in the regulation of sodium reabsorption in the kidney of Dahl salt-sensitive (DS) and salt-resistant Brown-Norway (BN) and consomic rats (SS.BN13), in which chromosome 13 from the BN rat has been introgressed into the DS genetic background. The expression of the Na+/K+/2Cl- (BSC-1) cotransporter, Na+/H+ exchanger (NHE3), and Na+-K+-ATPase proteins were similar in the renal cortex of DS, BN, and SS.BN13 rats fed either a low-salt (0.1% NaCl) or a high-salt (8% NaCl) diet. The expression of the BSC-1 and the renal outer medullary K+ channel (ROMK) were higher, whereas the expression of the cytochrome P4504A proteins responsible for the formation of 20-hydroxyeicosatetraenoic (20-HETE) was lower in the outer medulla of the kidney of DS than in BN or SS.BN13 rats fed either a low-salt or a high-salt diet. In addition, the renal formation and excretion of 20-HETE was lower in DS than in BN and SS.BN13 rats. These results suggest that overexpression of ROMK and BSC-1 in the thick ascending limb combined with a deficiency in renal formation of 20-HETE may predispose Dahl S rats fed a high-salt diet to Na+ retention and hypertension.
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PMID:Elevated BSC-1 and ROMK expression in Dahl salt-sensitive rat kidneys. 1496 39

Dopamine D(1)-mediated inhibition of Na(+),K(+)-ATPase activity in opossum kidney (OK) cells involves the sequential activation of the adenylyl cyclase-protein kinase A (PKA) and the phospholipase C-protein kinase C (PKC) pathways. The present study evaluated the signalling cascades involved in dopamine-mediated inhibition of Na(+)/H(+) exchanger isoform 3 (NHE3) in OK cells. The transport kinetics displayed a simple Michaelis-Menten relationship for extracellular Na(+) of 25+/-6 mM. Dopamine and the dopamine D(1)-like receptor agonist SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) inhibited NHE3 activity in a concentration-dependent manner; the dopamine D(2)-like receptor agonist quinerolane was devoid of effect. The SKF 38393-mediated inhibition of NHE3 was prevented either by the dopamine D(1)-like receptor antagonist SKF 83566 ((+/-)-7-Bromo-8-8-hydroxy-3 methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 1 microM), overnight treatment with cholera toxin (500 ng/ml), the PKA antagonist H-89 (N-(2-[p-bromocinnamylamino]ethyl)-5 isoquinolinesulfonamide hydrochloride; 10 microM), the PKC antagonist chelerythrine (1 microM), or the phospholipase C inhibitor U-73,122 (1-(6-[(17beta]-3-methoxyestra-1,3,5[10]-trien-17-yl) amino] hexyl)-1H-pyrrole-2,5-dione; 3 microM). In addition, dibutyril cAMP (dB-cAMP; 500 microM) was found to increase phospholipase C activity, both in membranes and in cytosol from OK cells; in contrast, phorbol-12,13-dibutyrate (PDB) (1 microM) did not have a significant effect on phospholipase C activity. Pre-treatment of OK cells with the anti-G(s)alpha antibody, but not the anti-G(q/11)alpha antibody, blunted the inhibitory effect of SKF 38393 on NHE3 activity. It is concluded that dopamine D(1)-mediated inhibition of NHE3 in renal OK cells involves both adenylyl cyclase-PKA and the phospholipase C-PKC pathways, a mechanism similar to that described for Na(+),K(+)-ATPase.
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PMID:Dopamine acutely decreases type 3 Na(+)/H(+) exchanger activity in renal OK cells through the activation of protein kinases A and C signalling cascades. 1504 35

Nephrotic syndrome is often accompanied by sodium retention and generalized edema. However, the molecular basis for the decreased renal sodium excretion remains undefined. We hypothesized that epithelial Na channel (ENaC) subunit dysregulation may be responsible for the increased sodium retention. An experimental group of rats was treated with puromycin aminonucleoside (PAN; 180 mg/kg iv), whereas the control group received only vehicle. After 7 days, PAN treatment induced significant proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and extensive ascites. The protein abundance of alpha-ENaC and beta-ENaC was increased in the inner stripe of the outer medulla (ISOM) and in the inner medulla (IM) but was not altered in the cortex. gamma-ENaC abundance was increased in the cortex, ISOM, and IM. Immunoperoxidase brightfield- and laser-scanning confocal fluorescence microscopy demonstrated increased targeting of alpha-ENaC, beta-ENaC, and gamma-ENaC subunits to the apical plasma membrane in the distal convoluted tubule (DCT2), connecting tubule, and cortical and medullary collecting duct segments. Immunoelectron microscopy further revealed an increased labeling of alpha-ENaC in the apical plasma membrane of cortical collecting duct principal cells of PAN-treated rats, indicating enhanced apical targeting of alpha-ENaC subunits. In contrast, the protein abundances of Na(+)/H(+) exchanger type 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (BSC-1), and thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC) were decreased. Moreover, the abundance of the alpha(1)-subunit of the Na-K-ATPase was decreased in the cortex and ISOM, but it remained unchanged in the IM. In conclusion, the increased or sustained expression of ENaC subunits combined with increased apical targeting in the DCT2, connecting tubule, and collecting duct are likely to play a role in the sodium retention associated with PAN-induced nephrotic syndrome. The decreased abundance of NHE3, BSC-1, TSC, and Na-K-ATPase may play a compensatory role to promote sodium excretion.
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PMID:Increased expression and apical targeting of renal ENaC subunits in puromycin aminonucleoside-induced nephrotic syndrome in rats. 1507 88

Transgenic mice targeted for the c-ros gene, which are fertile when heterozygous (HET), but infertile when homozygous (knockout, KO) and associated with failure in pubertal differentiation of the epididymal initial segment, provide a model for studying the role of the epididymal luminal environment in sperm development. Luminal fluid from the cauda epididymidis was measured by both ion-selective microelectrodes and pH strips to be 0.3 pH units higher in the KO than HET. Of the genes responsible for luminal acidification, expression of mRNA of vacuolar H(+)-ATPase was found in all epididymal regions, but with no difference between KO and HET. Immunohistochemistry showed its presence in epithelial apical cells and clear cells. The Na(+)-hydrogen exchanger NHE2 was expressed at mRNA and protein levels in the caput but only marginally detectable if at all in the distal epididymis. This was compensated for by NHE3 which was expressed strongest in the cauda region, in agreement with immunohistochemical staining. Quantification of Western blot data revealed slight, but significant, decreases of NHE2 in the caput and of NHE3 in the cauda in the KO mice. The increase in luminal fluid pH in the KO mice could also be contributed to by other epithelial regulating factors including the Na(+)-dependent glutamate transporter EAAC1 formerly reported to be down regulated in the KO.
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PMID:Increased luminal pH in the epididymis of infertile c-ros knockout mice and the expression of sodium-hydrogen exchangers and vacuolar proton pump H+-ATPase. 1509 36

Diabetic kidney disease is initially associated with hypertension and increased urinary albumin excretion. The hypertension is mediated by enhanced volume expansion due to enhanced salt and water retention by the kidney. The increased urinary albumin is not only due to increased glomerular leak, but also to a decrease in albumin reabsorption by the proximal tubule. The precise molecular mechanisms underlying these two phenomena and whether there is any link between the increase in Na(+) retention and proteinuria remain unresolved. There is significant evidence to suggest that increased Na(+) retention by the proximal tubule Na(+)/H(+) exchanger isoform 3 (NHE3) can play a role in some forms of hypertension. Increased NHE3 activity in models of diabetes mellitus may explain, in part, the enhanced salt retention observed in patients with diabetic kidney disease. The NHE3 also plays a role in receptor-mediated albumin uptake in the proximal tubule. The uptake of albumin requires the assembly of a macromolecular complex that is thought to include the megalin/cubulin receptor, NHE3, the vacuolar type H(+)-ATPase (v-H(+)-ATPase), the Cl(-) channel ClC-5 and interactions with the actin cytoskeleton. The NHE3 seems to exist in two functionally distinct membrane domains, one involved with Na(+) reabsorption and the other involved in albumin uptake. The present review focuses on the evidence derived from in vivo studies, as well as complementary studies in cell culture models, for a dual role of NHE3 in both Na(+) retention and albumin uptake. We suggest a possible mechanism by which disruption of the proximal tubule albumin uptake mechanism in diabetes mellitus may lead to both increased Na(+) retention and proteinuria.
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PMID:Molecular changes in proximal tubule function in diabetes mellitus. 1519 16

This study evaluated the transduction pathway associated with type 3 Na(+)/H(+) exchanger (NHE3) activity-induced inhibition during dopamine D(3) receptor activation in immortalized renal proximal tubular epithelial cells from the spontaneously hypertensive rat. The dopamine D(3) receptor agonist 7-OH-DPAT decreased NHE3 activity, which was prevented by the D(2)-like receptor antagonist S-sulpiride, pertussis toxin (PTX; overnight treatment), and the PKC inhibitor chelerythrine, but not by cholera toxin (overnight treatment), the MAPK inhibitor PD-098059, or the p38 inhibitor SB-203580. The PKA inhibitor H-89 abolished the inhibitory effects of forskolin on NHE3 activity, but not that of 7-OH-DPAT. The phospholipase C (PLC) inhibitor U-73122 prevented the inhibitory effects of 7-OH-DPAT, whereas PDBu and 7-OH-DPAT increased PLC activity and reduced NHE3 activity; downregulation of PKC abolished the inhibitory effects of both PDBu and 7-OH-DPAT on NHE activity. The inhibition of NHE3 activity by GTPgammaS and the prevention of the effect of 7-OH-DPAT by PTX suggest an involvement of a G(i/o) protein coupled to the dopamine D(3) receptor. Indeed, the 7-OH-DPAT-induced decrease in NHE3 activity was abolished in cells treated overnight with the anti-G(i)alpha3 antibody, but not in cells treated with antibodies against G(q/11), G(s)alpha, G(beta), and G(i)alpha1,2 proteins. The calcium ionophore A-23187 and the Ca(2+)-ATPase inhibitor thapsigargin increased intracellular Ca(2+) but did not affect NHE3 activity. However, the inhibitory effects of PDBu and 7-OH-DPAT on NHE3 activity were completely abolished by A-23287 and thapsigargin. It is concluded that inhibition of NHE3 activity by dopamine D(3) receptors coupled to G(i)alpha3 proteins is a PLC-PKC-mediated event, modulated by intracellular Ca(2+).
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PMID:Gialpha3 protein-coupled dopamine D3 receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event. 1526 66

Inner ear physiology is reviewed with emphasis on features common to renal physiology. Genetic disorders in transporters/channels for chloride (ClC-K), bicarbonate (Cl(-)/HCO(3)(-) exchanger), protons (H(+)-ATPase), sodium (ENaC, NKKC1, NBC3, NHE3), potassium (KCNQ1/KCNE1, Kcc4), and water (AQP4) in the inner ear and their relation to the kidney are discussed. Based on data from human disorders (with or without mouse counterparts) and mouse models (without human counterparts) this article focuses on the involvement of these transporters/channels in hearing loss.
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PMID:Genetic disorders of transporters/channels in the inner ear and their relation to the kidney. 1536 6

The Na(+)/phosphate cotransporter NaPi-IIa (SLC34A1) is the major transporter mediating the reabsorption of P(i) in the proximal tubule. Expression and activity of NaPi-IIa is regulated by several factors, including parathyroid hormone, dopamine, metabolic acidosis, and dietary P(i) intake. Dopamine induces natriuresis and phosphaturia in vivo, and its actions on several Na(+)-transporting systems such as NHE3 and Na(+)-K(+)-ATPase have been investigated in detail. Using freshly isolated mouse kidney slices, perfused proximal tubules, and cultured renal epithelial cells, we examined the acute effects of dopamine on NaPi-IIa expression and localization. Incubation of isolated kidney slices with the selective D(1)-like receptor agonists fenoldopam (10 microM) and SKF-38393 (10 microM) for 1 h induced NaPi-IIa internalization and reduced expression of NaPi-IIa in the brush border membrane (BBM). The D(2)-like selective agonist quinpirole (1 microM) had no effect. The D(1) and D(2) agonists did not affect the renal Na(+)/sulfate cotransporter NaSi in the BBM of the proximal tubule. Studies with isolated perfused proximal tubules demonstrated that activation of luminal, but not basolateral, D(1)-like receptors caused NaPi-IIa internalization. In kidney slices, inhibition of PKC (1 microM chelerythrine) or ERK1/2 (20 microM PD-098089) pathways did not prevent the fenoldopam-induced internalization. Inhibition with the PKA blocker H-89 (10 microM) abolished the effect of fenoldopam. Immunoblot demonstrated a reduction of NaPi-IIa protein in BBMs from kidney slices treated with fenoldopam. Incubation of opossum kidney cells transfected with NaPi-IIa-green fluorescent protein chimera shifted fluorescence from the apical membrane to an intracellular pool. In summary, dopamine induces internalization of NaPi-IIa by activation of luminal D(1)-like receptors, an effect that is mediated by PKA.
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PMID:Activation of dopamine D1-like receptors induces acute internalization of the renal Na+/phosphate cotransporter NaPi-IIa in mouse kidney and OK cells. 1554 13

Vasopressin and ANG II, which are known to play a major role in renal water and sodium reabsorption, are mainly coupled to the cAMP/PKA and phosphoinositide pathways, respectively. There is evidence for cross talk between these intracellular signaling pathways. We therefore hypothesized that vasopressin-induced water reabsorption could be attenuated by ANG II AT(1) receptor blockade in rats. To address this, three protocols were used: 1) DDAVP treatment (20 ng/h sc for 7 days, n = 8); 2) DDAVP (20 ng/h sc for 7 days) and candesartan (1 mg.kg(-1).day(-1) sc for 7 days) cotreatment (n = 8); and 3) vehicle infusion as the control (n = 8). All rats were maintained on a NaCl-deficient diet (0.1 meq Na(+).200 g body wt(-1).day(-1)) during the experiment. DDAVP treatment alone resulted in a significant decrease in urine output (3.1 +/- 0.2 ml/day) compared with controls (11.5 +/- 2.2 ml/day, P < 0.05), whereas the urine output was significantly increased in response to DDAVP and candesartan cotreatment (9.8 +/- 1.0 ml/day, P < 0.05). Consistent with this, rats cotreated with DDAVP and candesartan demonstrated decreased urine osmolality (1,319 +/- 172 mosmol/kgH(2)O) compared with rats treated with DDAVP alone (3,476 +/- 182 mosmol/kgH(2)O, P < 0.05). Semiquantitative immunoblotting revealed significantly decreased expression of medullary aquaporin-2 (AQP2) and AQP2 phosphorylated in the PKA phosphorylation consensus site Ser-256 (p-AQP2) in response to DDAVP and candesartan cotreatment compared with DDAVP treatment alone. In addition, cortical and medullary AQP1 was also downregulated. Fractional sodium excretion (FE(Na)) and plasma potassium levels were markedly increased, and the expressions of the cortical type 3 Na(+)/H(+) exchanger (NHE3), thiazide-sensitive Na-Cl cotransporter (NCC), and Na-K-ATPase were significantly decreased in response to DDAVP and candesartan cotreatment. Moreover, medullary type 1 bumetanide-sensitive Na-K-2Cl cotransporter expression showed a marked gel mobility shift from 160 to approximately 180 kDa corresponding to enhanced glycosylation, whereas expression was unchanged. In conclusion, ANG II AT(1) receptor blockade in DDAVP-treated rats was associated with decreased urine concentration and decreased AQP2 and AQP1 expression. Moreover, FE(Na) was increased in parallel with decreased expression of NHE3, NCC, and Na-K-ATPase. These results suggest that ANG II AT(1) receptor activation plays a significant role in regulating aquaporin and sodium transporter expression and modulating urine concentration in vivo.
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PMID:Angiotensin II AT1 receptor blockade decreases vasopressin-induced water reabsorption and AQP2 levels in NaCl-restricted rats. 1558 68


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