Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal glucose handling in the proximal tubule may play an important role in the development of diabetic nephropathy. Thus, the present study was designed to examine the effect of high glucose on alpha-methyl-D-glucopyranoside (alpha-MG) uptake and its signaling pathways in the primary cultured rabbit renal proximal tubule cells (PTCs). When PTCs were preincubated with 25 or 50 mM glucose for 4 h, 25 or 50 mM glucose significantly inhibited alpha-MG uptake, while 25 or 50 mM mannitol and L-glucose did not affect. Actinomycin D and cycloheximide did not block the effect of high glucose on alpha-MG uptake. Twenty-five millimoles glucose-induced inhibition of alpha-MG uptake was blocked by mepacrine and AACOCF(3), phospholipase A(2) (PLA(2)) inhibitors. Twenty-five millimoles of glucose, not mannitol or L-glucose, significantly increased the [(3)H]-arachidonic acid (AA) release compared to control. In addition, the 25 mM glucose-induced [(3)H]-AA release was completely blocked by mepacrine or AACOCF(3). Indomethacin, a cyclooxygenase inhibitor, blocked the high glucose-induced inhibition of alpha-MG uptake, although econazole, cytochrome P-450 a epoxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, did not. On the other hand, staurosporine and bisindolylmaleimide I, protein kinase C (PKC) inhibitors, blocked 25 mM glucose-induced increase of [(3)H]-AA release and inhibition of alpha-MG uptake. However, neomycin, U 73122, and phospholipase c(PLC) inhibitors did not block the effect of 25 mM glucose on [(3)H]-AA release and alpha-MG uptake. Pretreatment of methoxyverapamil, an L-type Ca(2+) channel blocker, abolished 25 mM glucose-induced increase of [(3)H]-AA release. Indeed, 25 mM glucose increased translocation of cPLA(2) from cytosolic fraction to membrane fraction. In conclusion, the present results demonstrate that high glucose inhibits alpha-MG uptake by the increase of AA release via the activation of PKC.
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PMID:High glucose-induced inhibition of alpha-methyl-D-glucopyranoside uptake is mediated by protein kinase C-dependent activation of arachidonic acid release in primary cultured rabbit renal proximal tubule cells. 1079 10

Eicosanoids regulate various cellular functions that are important in physiological and pathophysiological processes. Arachidonic acid is released from membranes by phospholipase A(2) (PLA(2)) activity. Activated macrophages derived from mice lacking the 85-kDa group IV cytosolic PLA(2) (cPLA(2)) have a markedly reduced release of prostaglandin E(2) and leukotrienes B(4) and C(4). Under basal conditions and after furosemide, urinary prostaglandin E(2) excretion is reduced in cPLA(2)-knockout (cPLA(2)(-/-)) mice. Serum creatinine, Na(+), K(+), and Ca(2+) concentrations, glomerular filtration rate, and fractional excretion of Na(+) and K(+) are not different in cPLA(2)(-/-) and cPLA(2)(+/+) mice. Maximal urinary concentration is lower in 48-h water-deprived cPLA(2)(-/-) mice compared with cPLA(2)(+/+) animals (1,934 +/- 324 vs. 3,541 +/- 251 mmol/kgH(2)O). Plasma osmolality is higher (337 +/- 5 vs. 319 +/- 3 mmol/kgH(2)O) in cPLA(2)(-/-) mice that lose a greater percentage of their body weight (20 +/- 2 vs. 13 +/- 1%) compared with cPLA(2)(+/+) mice after water deprivation. Vasopressin does not correct the concentrating defect. There is progressive reduction in urinary osmolality with age in cPLA(2)(-/-) mice. Membrane-associated aquaporin-1 (AQP1) expression, identified by immunocytochemical techniques, is reduced markedly in proximal tubules of older cPLA(2)(-/-) animals but is normal in thin descending limbs. However, Western blot analysis of kidney cortical samples revealed an equivalent AQP1 signal intensity in cPLA(2)(+/+) and cPLA(2)(-/-) animals. Young cPLA(2)(-/-) mice have normal proximal tubule AQP1 staining. Collecting duct AQP2, -3, and -4 were normally expressed in the cPLA(2)(-/-) mice. Thus mice lacking cPLA(2) develop an age-related defect in renal concentration that may be related to abnormal trafficking and/or folding of AQP1 in the proximal tubule, implicating cPLA(2) in these processes.
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PMID:Renal concentrating defect in mice lacking group IV cytosolic phospholipase A(2). 1124 52

The influence of different polychlorinated biphenyls (PCBs) upon the cytosolic phospholipase A(2) (cPLA(2)) redistribution to the particulate fraction has been investigated in rat renal proximal tubule culture cells. Treatment with Aroclor 1248 increased PLA(2) activity in the particulate fraction in a concentration-dependent manner using two radioactive substrates. However, the activity of PLA(2) in the cytosolic fraction decreased. This work also shows that 2,2',4,4',5,5'-hexachlorobiphenyl (HCB) (a di-ortho-substituted nonplanar congener) can increase the activity of PLA(2) in the particulate fraction and decrease the enzyme activity in the cytosolic fraction. The exposure of cell cultures to 3,3',4,4'-tetrachlorobiphenyl (TCB) (a non-ortho-subtituted planar congener) does not alter PLA(2) activity. These results suggest that PCBs, depending on their planar or nonplanar structures, cause a translocation of the enzyme from the cytosol to membranes. To evaluate this possibility, the contents of immunoreactive cPLA(2) were examined by immunoblot analysis in the high-speed supernatant and the particulate fraction of treated cell cultures. The increases/decreases in the amounts of cPLA(2) protein agree with the increases/decreases of PLA(2) activity previously cited. These data demonstrate that the PCB-stimulated redistribution of cPLA(2) to membranes is associated, at least in part, with the changes detected in the activity of the enzyme.
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PMID:Redistribution of cPLA(2) in rat renal tubular cell cultures in response to PCBs. 1125 55

Phospholipase A(2) (PLA(2)) hydrolyzes the sn-2 ester bond in phospholipids, releasing a fatty acid and a lysophospholipid. Recently, a novel 85-kDa membrane-bound-Ca(2+)-independent PLA(2) (iPLA(2)) was identified in insect and bacterial cells transfected with candidate PLA(2) sequences. However, few data exist demonstrating a membrane-bound-iPLA(2) in mammalian cells, its subcellular localization, or its physiological role. Herein, we demonstrate the expression of an 85-kDa endoplasmic reticulum (ER)-Ca(2+)-iPLA(2) (ER-iPLA(2)) in rabbit renal proximal tubule cells (RPTC) that is plasmalogen selective and is inhibited by the specific Ca(2+)-iPLA(2) inhibitor bromoenol lactone (BEL). RPTC exposed to tert-butylhydroperoxide for 24 h exhibited 20% oncosis compared with 2% in controls. Inhibition of ER-iPLA(2) with BEL before tert-butylhydroperoxide exposure resulted in 50% oncosis. To determine whether this effect was common to oxidants, we tested the ability of BEL to potentiate oncosis induced by cumene hydroperoxide, menadione, duraquinone, cisplatin, and the nonoxidant antimycin A. All oxidants tested produced oncosis after 24 h, and prior inhibition of ER-iPLA(2) potentiated oncosis at least twofold. In contrast, inhibition of ER-iPLA(2) did not alter antimycin A-induced oncosis. Lipid peroxidation increased from 1.4- to 5.2-fold in RPTC treated with BEL before oxidant exposure, whereas no change was seen in antimycin A-treated RPTC. These results are the first to demonstrate the expression and subcellular localization of an ER-iPLA(2). These results also suggest that ER-iPLA(2) functions to protect against oxidant-induced lipid peroxidation and oncosis.
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PMID:Role of an endoplasmic reticulum Ca(2+)-independent phospholipase A(2) in oxidant-induced renal cell death. 1216

Epidermal growth factor (EGF) is known to play an important role in modulating renal transport functions. Thus, we investigated the effect of EGF on Ca(2+) uptake and its related signals in the primary cultured rabbit renal proximal tubule cells. EGF (50 ng/ml, 1 h) stimulated Ca(2+) uptake. Its effect was blocked by AG 1478 (an EGF receptor antagonist), genistein or herbimycin A (tyrosine kinase inhibitors). EGF increased intracellular cAMP level and SQ 22536 (an adenylate cyclase inhibitor), Rp-cAMP (a cAMP analogue), or PKI (a protein kinase A inhibitor) blocked the EGF-induced stimulation of Ca(2+) uptake. EGF-induced stimulation of Ca(2+) uptake was also blocked by neomycin or U-73122 (phospholipase C inhibitors), staurosporine, H-7, or bisindolylmaleimide I (protein kinase C inhibitors), nifedipine or methoxyverapamil (L-type Ca(2+) channel blockers). It increased IPs formation by 167 +/- 5% compare to control within 90 s. On the other hand, EGF increased [(3)H]-arachidonic acid release, which was significantly blocked by PKC inhibitors. In addition, PGE(2), one of cyclooxygenase metabolites, and 5,6-EET, one of cytochrome P-450 metabolites, increased Ca(2+) uptake. These results suggest that cAMP, PLC/PKC, and PLA(2) are involved in EGF-induced stimulation of Ca(2+) uptake.
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PMID:Epidermal growth factor regulates Ca2+ uptake in primary cultured renal proximal tubule cells: involvement of cAMP, PKC and cPLA2. 1288 43

It has been demonstrated recently that rabbit renal proximal tubule cells (RPTC) express a novel Ca(2+)-independent phospholipase A(2) (iPLA(2)) whose activity localizes to the endoplasmic reticulum (ER-iPLA(2)) and is similar to group VIB PLA(2). In this study, the expression of group VIB PLA(2) was examined and the role of ER-iPLA(2) in cisplatin-induced apoptosis was determined. Cisplatin induced both time- and concentration-dependent RPTC apoptosis as determined by p53 nuclear localization, annexin V staining, caspase 3 activity, and chromatin condensation. Inhibition of ER-iPLA(2) with bromoenol lactone (5 microM) reduced cisplatin-induced annexin V binding 40%, chromatin condensation 55%, and caspase 3 activity 42%, but had no effect on p53 nuclear localization. Treatment of RPTC with the protein kinase C stimulator phorbol 12-myristate 13-acetate increased the activity of ER-iPLA(2) 2-fold and increased cisplatin-induced RPTC apoptosis. These studies demonstrate that group VIB PLA(2) is expressed in RPTC and suggest that RPTC ER-iPLA(2) is the rabbit homolog of group VIB PLA(2). These data also demonstrate that ER-iPLA(2) acts downstream of p53 and upstream of caspase 3 to mediate cisplatin-induced RPTC apoptosis. Finally, ER-iPLA(2) seems to be regulated by protein kinase C.
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PMID:Role of an endoplasmic reticulum Ca2+-independent phospholipase A2 in cisplatin-induced renal cell apoptosis. 1463 37

Basolateral transport of organic anions (OAs) into mammalian renal proximal tubule cells is a tertiary active transport process. The final step in this process involves movement of OA into the cells against its electrochemical gradient in exchange for alpha-ketoglutarate (alphaKG) moving down its electrochemical gradient. Two homologous transport proteins (OAT1 and OAT3) that function as basolateral OA/alphaKG exchangers have been cloned and sequenced. We are in the process of determining the functional distribution and regulation of OAT1 and OAT3 in renal tubules. We are using rabbit OAT1 (rbOAT1) and OAT3 (rbOAT3) expressed in heterologous cell systems to determine substrate specificity and putative regulatory steps and isolated rabbit proximal renal tubule segments to determine functional distribution and physiological regulation of these transporters within their native epithelium. Rabbit OAT1 and OAT3 differ distinctly in substrate specificity. For example, rbOAT1 has a high affinity for the classical renal OA transport substrate, p-aminohippurate (PAH), whereas rbOAT3 has no affinity for PAH. In contrast, rbOAT3 has a high affinity for estrone sulfate (ES), whereas rbOAT1 has only a very slight affinity for ES. Both rbOAT1 and rbOAT3 appear to have about the same affinity for fluorescein (FL). These differences and similarities in substrate affinities make it possible to functionally map transporters along the renal tubules. Initial data indicate that OAT1 predominates in S2 segments of the rabbit proximal tubules, but studies of other segments are just beginning. Transport of a given substrate in any tubule segment depends on both the affinity of each transporter which can accept that substrate as well as the level of expression of each of those processes in that particular tubule segment. Basolateral PAH transport (presumably OAT1 activity) appears to be down-regulated by activation of protein kinase C (PKC) and up-regulated via mitogen-activated protein kinase (MAPK) through phospholipase A(2) (PLA(2)), prostaglandin E(2) (PGE(2)), cyclic AMP, and protein kinase A (PKA) activation.
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PMID:The molecular and cellular physiology of basolateral organic anion transport in mammalian renal tubules. 1472 55

The effect of EGF on (14)C-alpha-methyl-D-glucopyranoside (alpha-MG) uptake and its related signaling pathways were examined in primary cultured rabbit renal proximal tubule cells (PTCs). Epidermal growth factor (EGF) (50 ng/ml) was found to inhibit alpha-MG uptake, a distinctive proximal tubule marker. The EGF effect was blocked by AG1478 (an EGF receptor antagonist) or genistein and herbimycin (tyrosine kinase inhibitors), respectively. In addition, the EGF-induced inhibition of alpha-MG uptake was blocked by neomycin and U73122 (phospholipase C inhibitors) as well as staurosporine, H-7, and bisindolylmaleimide I (protein kinase C inhibitors). EGF was also observed to increase inositol phosphate formation. Furthermore, both the EGF-induced inhibition of alpha-MG uptake and increase of arachidonic acid (AA) release were blocked by AACOCF(3) (a cytosolic phospholipase A(2) inhibitor), indomethacin (a cyclooxygenase inhibitor), and econazole (a cytochrome P-450 epoxygenase inhibitor). We examined the involvement of mitogen-activated protein kinases (MAPKs) in mediating the effect of EGF on alpha-MG uptake. Indeed, EGF increased phosphorylation of p44/p42 MAPK and the EGF-induced inhibition of alpha-MG uptake as well as the stimulatory effect of EGF on AA release was blocked by PD 98059 (a p44/42 MAPK inhibitor), suggesting a causal relationship. However, inhibitors of PKC also prevented the EGF-induced increase of AA release. In conclusion, EGF partially inhibited alpha-MG uptake via PLC/PKC, p44/42 MAPK, and PLA(2) signaling pathways.
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PMID:Epidermal growth factor inhibits 14C-alpha-methyl-D-glucopyranoside uptake in renal proximal tubule cells: involvement of PLC/PKC, p44/42 MAPK, and cPLA2. 1504 3

Exposure of renal proximal tubule cells to oxalate may play an important role in cell proliferation, but the signaling pathways involved in this effect have not been elucidated. Thus the present study was performed to examine the effect of oxalate on (3)H-labeled thymidine incorporation and its related signal pathway in primary cultured rabbit renal proximal tubule cells (PTCs). The effects of oxalate on [(3)H]thymidine incorporation, lactate dehydrogenase (LDH) release, Trypan blue exclusion, H(2)O(2) release, activation of mitogen-activated protein kinases (MAPKs), and (3)H-labeled arachidonic acid (AA) release were examined in primary cultured renal PTCs. Oxalate inhibited [(3)H]thymidine incorporation in a time- and dose-dependent manner. However, its analogs did not affect [(3)H]thymidine incorporation. Oxalate (1 mM) significantly increased H(2)O(2) release, which was blocked by N-acetyl-l-cysteine (NAC) and catalase (antioxidants). Oxalate significantly increased p38 MAPK and stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK) activity, not p44/42 MAPK. Oxalate stimulated [(3)H]AA release and translocation of cytosolic phospholipase A(2) (cPLA(2)) from the cytosolic fraction to the membrane fraction. Indeed, oxalate significantly increased prostaglandin E(2) (PGE(2)) production compared with control. Oxalate-induced inhibition of [(3)H]thymidine incorporation and increase of [(3)H]AA release were prevented by antioxidants (NAC), a p38 MAPK inhibitor (SB-203580), a SAPK/JNK inhibitor (SP-600125), or PLA(2) inhibitors [mepacrine and arachidonyl trifluoromethyl ketone (AACOCF(3))], but not by a p44/42 MAPK inhibitor (PD-98059). These findings suggest that oxalate inhibits renal PTC proliferation via oxidative stress, p38 MAPK/JNK, and cPLA(2) signaling pathways.
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PMID:Oxalate inhibits renal proximal tubule cell proliferation via oxidative stress, p38 MAPK/JNK, and cPLA2 signaling pathways. 1522 3

Within the kidney, angiotensin II type 2 (AT(2)) receptor mediates phospholipase A(2) (PLA(2)) activation, arachidonic acid release, epidermal growth factor (EGF) receptor transactivation, and mitogen-activated protein kinase activation. Arachidonic acid mimics this transactivation by an undetermined mechanism. The role of c-Src in mediating angiotensin II and arachidonic acid signaling was determined by employing immunocomplex kinase assay, Western blotting analysis, and protein immunoblotting on co-precipitated EGF receptor (EGFR) proteins and agarose conjugates of glutathione S-transferase fusion proteins containing the c-Src homology 2 (SH2) and SH3 domains. Angiotensin II induced extracellular signal-regulated kinase (ERK) activation in primary cultures of rabbit proximal tubule cells via the activation of c-Src and association of the EGFR with the c-Src SH2 domain, effects that were mimicked by arachidonic acid and its inactive analogue eicosatetraynoic acid. Inhibition of PLA(2) by mepacrine and methyl arachidonyl fluorophosphate, AT(2) receptor by PD123319, Src family kinases by, 1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d] pyrimidine (PP2) and c-Src by overexpression of a dominant-negative mutant of c-Src abrogated these effects. However, inhibitors of arachidonic acid metabolic pathways did not block these effects. The present work provides a new and novel paradigm for transactivation of a kinase receptor linked to a fatty acid, which may apply to activation of a variety of phospholipases and accompanying arachidonic acid release.
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PMID:Arachidonic acid induces ERK activation via Src SH2 domain association with the epidermal growth factor receptor. 1659 96


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