Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For "leaky" epithelia the transepithelial resistance (Rt) is an electrophysiological measure of the paracellular pathway within the epithelial barrier. The Rt across a monolayer of LLC-PK1 porcine renal epithelial cells is specifically an inverse measure of paracellular transepithelial permeability and displays a multiphasic and reversible response to the cytokine tumor necrosis factor-alpha (TNF). The Rt response to TNF can be inhibited by the nonhydrolyzable adenosine 3',5'-cyclic monophosphate (cAMP) analogue, dibutyryl-cAMP. In addition, activation of adenylate cyclase (forskolin) or inhibition of phosphodiesterase (3-isobutyl-1-methylxanthine, Ro-20-1724, and pentoxifylline), each of which have been reported to elevate cellular cAMP levels, also inhibited the Rt response to TNF. Incubation of the LLC-PK1 cell sheet with N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, an inhibitor of cAMP-dependent protein kinase (PKA), potentiated the Rt response to TNF. The Rt response to TNF was completely prevented by preincubation of the cultures with cholera toxin, whereas pertussis toxin pretreatment had a slight but significant potentiating effect on the response. Pretreatment with cholera toxin was associated with an approximately 18-fold elevation in cAMP levels in both control and TNF-treated cultures. Measurements of cellular cAMP content at selected intervals after TNF administration showed a significant elevation (P < 0.01) of 140% above time-matched controls at 1 h after the administration of TNF to the cell sheet. The level of cAMP then declined to approximate control level within 2.5 h of TNF administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:cAMP modulates transepithelial resistance response of LLC-PK1 renal epithelia to tumor necrosis factor. 786 72

Addition of polyamines or their analogs to newly confluent LLC-PK1 cells resulted in down-regulation of Na(+)-dependent glucose transport (symport) activity. Polyamines prevented the induction of this symporter by the differentiation inducer hexamethylene bisacetamide (HMBA) but did not influence induction by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Partial depletion of endogenous polyamines after addition of alpha-difluoromethylornithine (DFMO) resulted in a 4 to 5-fold increase in symporter expression. Symporter induction by either HMBA or DFMO was inhibited by the protein kinase inhibitor H-7 but H-7 did not affect symporter induction by IBMX. Changes in symporter activity were accompanied by changes in levels of the 75 kD symporter subunit detected by Western blot. Cultures exposed to HMBA exhibited reduced levels of ornithine decarboxylase activity. Our results suggest that induction of symporter expression by HMBA may be mediated in part by its effects on polyamine metabolism, and point to parallel roles of polyamines and cyclic AMP in regulating the expression of this physiologically important renal transport system.
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PMID:Polyamine regulation of Na+/glucose symporter expression in LLC-PK1 cells. 838 Nov 24

The studies of animal models of nephrogenic diabetes insipidus (NDI) suggest that abnormally high activity of cAMP phosphodiesterase (cAMP-PDE), may cause unresponsiveness to the diuretic effect of AVP. We explored whether overexpression of one of the cAMP-PDE type isozymes, PDE-IV, in [8-Arg]-vasopressin (AVP) sensitive renal epithelial LLC-PK1 cells can prevent the hormone-elicited cAMP increase. LLC-PK1 cells were stably transfected with ratPDE3.1 cDNA (which encodes for rolipram-sensitive PDE-IV), inserted in plasmid pCMV5 and then were compared with sham-transfected LLC-PK1 cells and wild LLC-PK1 cells. In the stably transfected clone (LLC-PK1-S #16), the rolipram-sensitive PDE-IV activity was about five times higher than in controls, whereas activities of other types of PDEs were not different. The presence of cognate mRNA for PDE-IV was confirmed by Northern blot. Whereas in the control cells (wild LLC-PK1 cells and sham-transfected LLC-PK1 cells), the incubation with 10(-7) M AVP increased cAMP more than tenfold, the LLC-PK1-S#16 cells with overexpressed cAMP-PDE were resistant to cAMP-increasing effects of AVP and forskolin. However, in the same LLC-PK1-S#16 cells the cGMP increases in response to nitroprusside were not diminished. The AVP-dependent cAMP accumulation in LLC-PK1-S#16 cells with overexpressed PDE-IV was restored by addition of roliprams which decreased cAMP-PDE activity to the levels similar to those in wild LLC-PK1 cells and sham-transfected LLC-PK1-#A1 cells. In contrast, inhibitors of other PDE isozymes (PDE-I or PDE-III) had little or no effect. Our findings show that excessive activity of cAMP-PDE, in this case of isozyme PDE-IV, can cause resistance to AVP which is analogous to that observed in collecting ducts of mice with hereditary nephrogenic diabetes insipidus.
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PMID:ADH resistance of LLC-pk1 cells caused by overexpression of cAMP-phosphodiesterase type-IV. 839 Oct 97

We investigated the effects of a phosphodiesterase inhibitor and dibutyryl cAMP (dBcAMP) on the cell injury induced by cephaloridine (CER) in an established renal epithelial cell LLC-PK1. CER increased the leakage of lactate dehydrogenase (LDH) from LLC-PK1 cells to the medium and the level of lipid peroxidation in the cells. 3-Isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, increased cAMP content in LLC-PK1 cells and ameliorated the increase in LDH leakage induced by CER, dBcAMP reduced the cell injury induced by CER. Our results suggest that a signalling pathway of cAMP protects against CER-induced renal cell injury, which is probably due to generation of oxygen radicals.
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PMID:Amelioration by cAMP of cephaloridine-induced injury in the porcine kidney cell line LLC-PK1. 890 1

To confirm the intracellular signal transduction in regulation of alkaline phosphatase (ALP) activity by calcitonin in kidney tubular cells, effects of several inhibitors of cyclic nucleotide phosphodiesterase (PDE) isoenzymes and cyclic AMP-dependent protein kinase (PKA) on the action of salmon calcitonin in porcine kidney tubular epithelial cells LLC-PK1 were examined. A confluent culture of LLC-PK1 cells was treated with calcitonin and inhibitors in Dulbecco's modified Eagle's medium supplemented with 0.1% bovine serum albumin, and intracellular cyclic AMP content and ALP activity were measured after incubation for 30 min and 48 hr, respectively. Calcitonin and PDE 4 inhibitors increased cyclic AMP level and ALP activity in the cells, and PDE 4 inhibitors synergistically potentiated the effects of calcitonin. Calcitonin induced ALP activation by treatment for the first 1 hr, as well as continuous treatment for 48 hr, while it never increased the enzyme activity just after 1-hr exposure. Rolipram, an inhibitor of PDE 4 isoenzyme, induced ALP activation by itself and in combination with calcitonin by only a long term treatment (48 hr). The activation of ALP by calcitonin and rolipram each alone and in combination was completely abolished by a PKA inhibitor, H-89. These results confirm that calcitonin induces ALP activation through the cyclic AMP-PKA pathway and that PDE 4 isoenzyme is closely associated with the calcitonin-receptor system and plays a major role in hydrolysis of cyclic AMP produced in the kidney tubular cells.
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PMID:Role of phosphodiesterase 4 isoenzyme in alkaline phosphatase activation by calcitonin in porcine kidney LLC-PK1 cells. 954 Dec 82

Intestinal transport of the type III phosphodiesterase inhibitor cilostazol was characterized to evaluate the influence of secretory transporter. Intestinal absorption of cilostazol measured by the in situ closed loop method, showed regional differences, with high permeability in the upper part of the small intestine. Intestinal secretory transport of cilostazol at the ileum was tended to be decreased by the increase of tested concentration of cilostazol from 10 to 20 microM when evaluated by means of a Ussing-type chamber method with mounted rat intestinal tissues. Transcellular transport of cilostazol in the basolateral-to-apical direction in LLC-GA5-COL150 cells, which overexpress P-glycoprotein, was higher than that in parental LLC-PK1 cells. In addition, cilostazol reduced the basolateral-to-apical transport and increased the accumulation of [(3)H]daunomycin in LLC-GA5-COL150 cells. Accordingly, cilostazol was demonstrated to be transported by P-glycoprotein, while cilostazol is not likely to cause induction of the expression level of P-glycoprotein by the same manner with rifampin. Apical-to-basolateral transport of cilostazol in Caco-2 cells was increased in a low concentration range, followed by a decrease with further increase of the concentration, while the permeability coefficient of cilostazol was above 1 x 10(-6) cm/s at any concentration. Initial uptake of [(14)C]cilostazol by Caco-2 cells was temperature dependent and was reduced in the presence of unlabeled cilostazol, suggesting that apical uptake is also mediated by a transporter(s). In conclusion, intestinal absorption of cilostazol, which has a high absorptive permeability, may not be significantly hampered by efflux transporters, such as P-glycoprotein.
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PMID:Limited influence of P-glycoprotein on small-intestinal absorption of cilostazol, a high absorptive permeability drug. 1460 10

Lysophosphatidylcholine (LPC) has diverse biological activities through different mechanisms including its conversion into other types of lipid mediators such as lysophosphatidic acid and 2-arachidonoylglycerol. Previously, we found that a large portion of the fluorescent analog of alkyl type LPC (Bodipy-lysoPAF) on porcine kidney epithelial cells (LLC-PK1) was degraded to monoalkylglycerol by lysophospholipase C-like activity and then quickly internalized into the cells. In this study, we investigated whether exogenous fluorescently labeled LPC (NBD-LPC) itself was also metabolized and internalized by a similar mechanism. LLC-PK1 cells converted NBD-LPC to either NBD-MG, possibly due to lysophospholipase C-like activity of ecto-nucleotide pyrophosphatase/phosphodiesterase-6, or to free fatty acid (FA), due to lysophospholipase activity in the culture medium at both sites. The resultant NBD-MG was further degraded to NBD-FA by lipase activity before or after its uptake into the cells, and a portion of NBD-FA was finally released into the culture medium on the opposite side.
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PMID:Ecto-lysophospholipase C controls lysophospholipid uptake and metabolism in porcine kidney epithelial cell line LLC-PK1. 1878 48


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