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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to examine the signaling pathways for a low dose of angiotensin II (ANG II) on Na+ uptake of primary cultured rabbit renal proximal tubule cells (PTCs) in hormonally defined serum-free medium. The results were as follows; ANG II (10(-11) M) stimulated the proliferation of PTCs. 10(-11) M ANG II stimulated Na+ uptake by 20%, whereas 10(-9) M ANG II inhibited it by 20% (p < 0.05). The stimulatory effect of 10(-11) M ANG II on Na+ uptake was inhibited by amiloride (10(-3) M) and by losartan (ANG II receptor subtype 1 antagonist, 10(-8) M) but not by PD123319 (ANG II receptor subtype 2 antagonist, 10(-8) M). Pertussis toxin (PTX, 50 ng/ml) prevented the ANG II-induced stimulation of Na+ uptake (p < 0.01). 8-Bromoadenosine 3', 5'-cyclic monophosphate (8-Br-cAMP, 10(-6) M) did not affect Na+ uptake. SQ 22536 (adenylate cyclase inhibitor, 10(-6) M) also did not change the ANG II-induced stimulation of Na+ uptake. ANG II did not stimulate cAMP production. In contrast, 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.01 ng/ml) produced significant increase in Na+ uptake. When ANG II and TPA were added together to the PTCs, there was no additive effect on Na+ uptake. Staurosporine (calcium-dependant protein kinase C inhibitor, 10(-6) M) led to a complete inhibition of ANG II-induced stimulation of Na+ uptake. ANG II-treatment resulted in a 26% increase in total protein kinase C (PKC) activity. However, 10(-11) M ANG II did not change [Ca2+]i mobilization and [3H]-AA release while 10(-9) M ANG II increased both of them. In conclusion, the PTX-sensitive PKC pathway may be the main signaling cascade in the stimulatory effects of low dose of ANG II (10(-11) M) on Na+ uptake in the primary cultured rabbit renal proximal tubule cells in hormonally defined serum-free medium.
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PMID:A signaling pathway for stimulation of Na+ uptake induced by angiotensin II in primary cultured rabbit renal proximal tubule cells. 1008 51

The aim of this study was to test the hypothesis that in vivo administration of parathyroid hormone (PTH) provokes diuresis/natriuresis through redistribution of proximal tubule apical sodium cotransporters (NHE3 and NaPi2) to internal stores and inhibition of basolateral Na-K-ATPase activity and to determine whether the same cellular signals drive the changes in apical and basolateral transporters. PTH-(1-34) (20 U), which couples to adenylate cyclase (AC), phospholipase C (PLC), and phospholipase A2 (PLA2), or [Nle8,18,Tyr34]PTH-(3-34) (10 U), which couples to PLC and PLA2 but not AC, were given to anesthetized rats as an intravenous bolus followed by low-dose infusion (1 U. kg-1. min-1 for 1 h). Renal cortex membranes were fractionated on sorbitol density gradients. PTH-(1-34) increased urinary cAMP excretion 3-fold, urine output (V) 2.0 +/- 0.1-fold, and lithium clearance (CLi) 2.8 +/- 0.3-fold. With this diuresis/natriuresis, 25% of NHE3 and 18% of NaPi2 immunoreactivity redistributed from apical membranes to higher density fractions containing intracellular membrane markers, and basolateral Na-K-ATPase activity decreased 25%. [Nle8,18,Tyr34]PTH-(3-34) failed to increase V or CLi or to provoke redistribution of NHE3 or NaPi2, but it did inhibit Na-K-ATPase activity 25%. We conclude that in vivo PTH stimulates natriuresis/diuresis associated with internalization of apical NHE3 and NaPi2 and inhibition of Na-K-ATPase activity, that cAMP-protein kinase A stimulation is necessary for the natriuresis/diuresis and NHE3 and NaPi2 internalization, and that Na-K-ATPase inhibition is not secondary to depressed apical Na+ transport.
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PMID:In vivo PTH provokes apical NHE3 and NaPi2 redistribution and Na-K-ATPase inhibition. 1033 53

The signaling pathways involved in the regulation of glucocorticoid on Pi uptake were examined in primary cultured rabbit renal proximal tubule cells (PTCs). Dexamethasone (DEX, 10(-9) M) inhibited Pi uptake, although aldosterone, a mineralocorticoid, did not affect Pi uptake. Its effect was due to a 23% decrease in the V(max) value. DEX-induced inhibition of Pi uptake was prevented by actinomycin D, cycloheximide, and the glucocorticoid receptor antagonists, progesterone and cortexolone. SQ 22536 (adenylate cyclase inhibitor) and the myristoylated protein kinase A inhibitor amide 14-22 (PKI) did not block the DEX-induced inhibition of Pi uptake. Indeed, DEX did not affect cAMP production. However, neomycin and U 73122 (PLC inhibitors), staurosporine and bisindolylmaleimide I (PKC inhibitors) blocked the DEX-induced inhibition of Pi uptake. In addition, DEX increased the membrane-bound PKC activity from 2. 82+/-0.21 to 4.16+/-0.34 pmol/mg protein/min. These findings demonstrate that glucocorticoid inhibits Pi uptake and its effect is genomic and receptor-mediated and the activation of the PLC/PKC pathway is involved in its effect on the PTCs.
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PMID:Regulatory mechanisms of Na/Pi cotransporter by glucocorticoid in renal proximal tubule cells: involvement of cAMP and PKC. 1056 47

The effect of estradiol-17beta-BSA (E(2)-BSA) on Ca(2+) uptake and its related signal pathways were examined in the primary cultured rabbit kidney proximal tubule cells. E(2)-BSA (10(-9) M) significantly stimulated Ca(2+) uptake from 2 h by 13% and at 8 h by 35% as compared to control, respectively. This stimulatory effect of E(2)-BSA was not inhibited by tamoxifen (10(-8) M, an intracellular estrogen receptor antagonist), actinomycin D (10(-7) M, a transcription inhibitor), and cycloheximide (4 x 10(-5) M, a protein synthesis inhibitor). However, E(2)-BSA-induced stimulation of Ca(2+) uptake was blocked by methoxyverapamil (10(-6) M, an L-type calcium channel blocker) and 5-(N-ethyl-N-isopropyl)-amiloride (10(-5) M, a Na(+)/H(+) antiporter blocker). These results suggest that E(2)-BSA stimulates Ca(2+) uptake through nongenomic pathways. Thus, we investigated which signal pathways were related to E(2)-BSA-induced stimulation of Ca(2+) uptake. 8-Br-cAMP (10(-6) M) alone increased Ca(2+) uptake by 22% compared to control. When E(2)-BSA combined with 8-Br-cAMP, Ca(2+) uptake was not significantly stimulated compared to E(2)-BSA. SQ 22536 (10(-6) M, an adenylate cyclase inhibitor) and myristoylated protein kinase A inhibitor amide 14-22 (10(-6) M, a protein kinase A inhibitor) blocked E(2)-BSA-induced stimulation of Ca(2+) uptake and E(2)-BSA also increased cAMP generation by 26% of that of control. In addition, TPA (0.02 ng/ml, an artificial PKC promoter) stimulated the Ca(2+) uptake by 14%, and the cotreatment of TPA and E(2)-BSA did not significantly stimulate Ca(2+) uptake compared to E(2)-BSA. E(2)-BSA-induced stimulation of Ca(2+) uptake was blocked by U 73122 (10(-6) M, a phospholipase C inhibitor) or bisindolylmaleimide I (10(-6) M, a protein kinase C inhibitor). Indeed, E(2)-BSA stimulated PKC activity by 26%. In conclusion, E(2)-BSA (10(-9) M) stimulated Ca(2+) uptake by nongenomic action, which is mediated by cAMP and PKC pathways.
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PMID:Estradiol-17beta-BSA stimulates Ca(2+) uptake through nongenomic pathways in primary rabbit kidney proximal tubule cells: involvement of cAMP and PKC. 1069 64

We have investigated the nongenomic as well as the genomic effects of glucocorticoids on phosphate (Pi) uptake in primary rabbit renal proximal tubule cells (PTCs) and have defined the involved signaling pathways. In the present study, cortisol-BSA (cortisol-BSA) (>10(-9) M, 30 min) was found to inhibit Pi uptake in a time- and concentration-dependent manner. However, progesterone-BSA (P(4)-BSA), 17ss-estradiol-BSA (E(2)-BSA), testosterone-BSA (T(4)-BSA), aldosterone, P(4), E(2), and T(4) (10(-9) M, 1 h) had no effect on Pi uptake. In addition, cortisol-BSA (10(-9) M) did not affect either Na(+) uptake or alpha-methylglucopyranoside (alpha-MG) uptake. The cortisol-BSA-induced inhibition of Pi uptake was associated with a decrease in the V(max) for Pi uptake, rather than the K(m). The inhibitory effect of cortisol-BSA was not blocked either by actinomycin D (an inhibitor of transcription), cycloheximide (an inhibitor of translation), or classical glucocorticoid receptor antagonists (RU 486 or P(4)). The cortisol-BSA-induced inhibition of Pi uptake was blocked by two phospholipase C (PLC) inhibitors (neomycin or U73122), and two protein kinase C (PKC) inhibitors (staurosporine or bisindolylmaleimide I) but not by two adenylate cyclase/protein kinase A inhibitors [SQ 22536 (an adenylate cyclase inhibitor) or myristoylated protein kinase A inhibitor amide 14-22]. Furthermore, cortisol-BSA promoted the translocation of PKC from the cytosolic fraction to the membrane fraction, while having no effect on the activity of adenylate cyclase. Our observations may thus be interpreted as indicating that cortisol does indeed inhibit renal Pi uptake via a nongenomic mechanism, which involves the PLC/PKC pathway.
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PMID:Regulation of phosphate uptake in primary cultured rabbit renal proximal tubule cells by glucocorticoids: evidence for nongenomic as well as genomic mechanisms. 1115 43

Alteration of [Ca2+]i by hyperglycemia is implicated in the pathogenesis of diabetic nephropathy. However, the effect of high glucose on Ca2+ regulation in proximal tubule cells is not known. Thus, we examined the mechanisms by which high glucose regulates Ca2+ uptake in primary cultured rabbit renal proximal tubule cells. Glucose increased the Ca2+ uptake in a time- and dose-dependent manner. A stimulatory effect of high glucose on Ca2+ uptake is predominantly observed using 25 mM glucose (high glucose) after 1 h, while 25 mM glucose did not affect cell viability and lactate dehydrogenase release. However, 25 mM mannitol and L-glucose did not affect Ca2+ uptake as compared with controls. Nifedipine and methoxyverapamil (L-type Ca2+ channel blockers) blocked high-glucose-induced stimulation of Ca2+ uptake. High-glucose-induced stimulation of Ca2+ uptake was blocked by pertussis toxin, SQ-22536 (adenylate cyclase inhibitor), myristoylated amide 14-22 (protein kinase A inhibitor), neomycin and U-73122 (phospholipase C inhibitors), and staurosporine and bisindolylmaleimide I (protein kinase C inhibitors). In addition, KN-62 (a Ca2+/calmodulin-dependent protein kinase II inhibitor) and W-7 (a Ca2+/calmodulin antagonist) blocked high-glucose-induced stimulation of Ca2+ uptake. In conclusion, high glucose stimulates the Ca2+ uptake through L-type Ca2+ channels via G-protein-coupled adenylate cyclase/cAMP and phospholipase C/protein kinase C pathways.
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PMID:High glucose stimulates Ca2+ uptake via cAMP and PLC/PKC pathways in primary cultured renal proximal tubule cells. 1117 1

The kidney, and more specifically the proximal tubule, is the main site of elimination of cationic endogenous metabolites and xenobiotics. Although numerous studies exist on renal organic cation transport of rat and rabbit, no information is available from humans. Therefore, we examined organic cation transport and its regulation across the basolateral membrane of isolated human proximal tubules. mRNA for the cation transporters hOCT1 and hOCT2 as well as hOCTN1 and hOCTN2 was detected in these tubules. Organic cation transport across the basolateral membrane of isolated collapsed proximal tubules was recorded with the fluorescent dye 4-(4-dimethylamino)styryl-N-methylpyridinium (ASP(+)). Depolarization of the cells by rising extracellular K(+) concentration to 145 mm reduced ASP(+) uptake by 20 +/- 5% (n = 15), indicating its electrogeneity. The substrates of organic cation transport tetraethylammonium (K(i) = 63 microm) and cimetidine (K(i) = 11 microm) as well as the inhibitor quinine (K(i) = 2.9 microm) reduced ASP(+) uptake concentration dependently. Maximal inhibition reached with these substances was approximately 60%. Stimulation of protein kinase C with 1,2-dioctanoyl-sn-glycerol (DOG, 1 microm) or ATP (100 microm) inhibited ASP(+) uptake by 30 +/- 3 (n = 16) and 38 +/- 13% (n = 6), respectively. The effect of DOG could be reduced with calphostin C (0.1 microm, n = 7). Activation of adenylate cyclase by forskolin (1 microm) decreased ASP(+) uptake by 29 +/- 3% (n = 10). hANP (10 nm) or 8-bromo-cGMP (100 microm) also decreased ASP(+) uptake by 17 +/- 3 (n = 9) or 32 +/- 5% (n = 10), respectively. We show for the first time that organic cation transport across the basolateral membrane of isolated human proximal tubules, most likely mediated via hOCT2, is electrogenic and regulated by protein kinase C, the cAMP- and the cGMP-dependent protein kinases.
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PMID:Properties and regulation of organic cation transport in freshly isolated human proximal tubules. 1144 27

The effect of parathyroid hormone (PTH) and activation of protein kinase C (PKC) and protein kinase A (PKA) on transepithelial P(i) transport was examined in monolayers of chick proximal tubule cells in primary culture (PTCs). Acute exposure of the PTCs to PTH (10(-9) M, basolateral side) significantly decreased the net reabsorption of P(i) by approximately 66%. There was no effect after the addition of PTH to the luminal side. Activation of PKC by phorbol 12-myristate 13-acetate (PMA; 0.1 microM) dramatically decreased net P(i) reabsorption by approximately 60%. Bisindolylmaleimide I (BIM; 1 microM), a highly selective PKC inhibitor, prevented PMA-induced inhibition. Activation of adenylate cyclase/PKA by forskolin (10 microM) mimicked the effect of PTH by significantly reducing net P(i) reabsorption by one-half. Addition of H-89 (10 microM), a potent inhibitor of PKA, abolished forskolin-induced inhibition. PTH inhibition was blocked by either BIM or H-89. Tissue electrophysiology remained stable after all treatments. There was a decreased immunoreactivity of the luminal Na+-P(i) cotransporter NaPi-IIa after PTH treatment. These data indicate that PTH inhibition of P(i) reabsorption in this in vitro system is mediated by PKC and PKA.
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PMID:Regulation of transepithelial phosphate transport by PTH in chicken proximal tubule epithelium. 1174 32

Angiotensin II (ANG II), acting through angiotensin type I (AT(1)) receptors on apical and basolateral surfaces of proximal tubule epithelial cells, increases sodium reabsorption in proximal tubules. Apical and basolateral receptors internalize after exposure to ANG II, but the role of internalization in receptor signaling and transport is not well defined. To determine the role of receptor internalization in ANG II-mediated receptor signaling and sodium transport, we stably expressed full-length and truncated AT(1A) receptors in opossum kidney cells. After stimulation with ANG II, wild-type receptors on apical and basolateral surfaces rapidly internalized, inhibited adenylate cyclase, and increased transcellular sodium transport. Truncation of the cytoplasmic tail of the AT(1A) receptor (TL314) resulted in receptors that were expressed on apical and basolateral surfaces but did not internalize, inhibit adenylate cyclase, or increase sodium transport. Because the cytoplasmic tail contains putative G protein coupling sites, mutant receptors that leave G protein interaction sites intact were designed. Cells expressing the truncation (TK333) or deletion (Del 315-329) also failed to internalize. When ANG II was added to basolateral surfaces of TK333 or Del 315-329, adenylate cyclase activity was inhibited and sodium transport was increased. In contrast, apical addition of ANG II was not associated with decreases in adenylate cyclase or increases in sodium transport. In conclusion, internalization pathways are important for AT(1A) receptor function in polarized proximal tubule epithelial cells. Apical AT(1A) receptors internalize before they interact with G proteins and signal cAMP. In contrast, basolateral AT(1A) receptors interact with G proteins and signal cAMP without internalizing.
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PMID:Role of internalization in AT(1A) receptor function in proximal tubule epithelium. 1188 Mar 23

Glucagon is known to affect glomerular filtration rate and renal tubular solute and fluid transport, although it is only thought to act directly on the thick ascending limb (TAL) and collecting duct (CD). Indeed, previous studies have detected glucagon-sensitive adenylate cyclase exclusively in these nephron segments, suggesting the presence of glucagon receptors. In the present study, we have demonstrated for the first time that glucagon receptor mRNA is expressed in the rat proximal tubule, as well as in the TAL and CD. By autoradiography, we have also shown that specific binding of glucagon occurs in both the renal cortex and medulla. In addition, using proximal tubule brush-border membrane (BBM) vesicles for studies of glucose transport, we have established that glucagon stimulates glucose uptake via a facilitative GLUT-mediated transport process (by 58%; P < 0.005), whereas cAMP stimulates only the sodium glucose-linked transporter ('SGLT')-mediated glucose uptake (by 53%; P < 0.05). Taken together, these findings suggest that glucagon could have a role in controlling proximal tubular transport function, including glucose reabsorption, but unlike in the TAL and CD, the proximal tubule glucagon receptor might not be coupled primarily to adenylate cyclase.
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PMID:Detection of glucagon receptor mRNA in the rat proximal tubule: potential role for glucagon in the control of renal glucose transport. 1260 82


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