Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone (PTH) inhibits Na+-K+-ATPase activity by serine phosphorylation of the alpha1 subunit through protein kinase C (PKC)- and extracellular signal-regulated kinase (ERK)-dependent pathways. Based on previous studies we postulated that PTH regulates sodium pump activity through isoform-specific PKC-dependent activation of ERK. In the present work utilizing opossum kidney cells, a model of renal proximal tubule, PTH stimulated membrane translocation of PKCalpha by 102 +/- 16% and PKCbetaI by 41 +/- 7% but had no effect on PKCbetaII and PKCzeta. Both PKCalpha and PKCbetaI phosphorylated the Na+-K+-ATPase alpha1 subunit in vitro. PTH increased the activity of PKCalpha but not PKCbetaI. Coimmunoprecipitation assays demonstrated that treatment with PTH enhanced the association between Na+-K+-ATPase alpha1 subunit and PKCalpha, whereas the association between Na+-K+-ATPase alpha1 subunit and PKCbetaI remained unchanged. A PKCalpha inhibitory peptide blocked PTH-stimulated serine phosphorylation of the Na+-K+-ATPase alpha1 subunit and inhibition of Na+-K+-ATPase activity. Pharmacologic inhibition of MEK-1 blocked PTH-stimulated translocation of PKCalpha, whereas transfection of constitutively active MEK-1 cDNA induced translocation of PKCalpha and increased phosphorylation of the Na+-K+-ATPase alpha1 subunit. In contrast, PTH-stimulated ERK activation was not inhibited by pretreatment with the PKCalpha inhibitory peptide. Inhibition of PKCalpha expression by siRNA did not inhibit PTH-mediated ERK activation but significantly reduced PTH-mediated phosphorylation of the Na+-K+-ATPase alpha1 subunit. Pharmacologic inhibition of phosphoinositide 3-kinase blocked PTH-stimulated ERK activation, translocation of PKCalpha, and phosphorylation of the Na+-K+-ATPase alpha1 subunit. We conclude that PTH stimulates Na+-K+-ATPase phosphorylation and decreases the activity of Na+-K+-ATPase by ERK-dependent activation of PKCalpha.
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PMID:Parathyroid hormone-mediated regulation of Na+-K+-ATPase requires ERK-dependent translocation of protein kinase Calpha. 1563 80

Cisplatin is an important chemotherapeutic agent but can cause acute renal injury. Part of this acute renal injury is mediated through tumor necrosis factor-alpha (TNF-alpha). The pathway through which cisplatin mediates the production of TNF-alpha and injury is not known. Cisplatin activates p38 MAPK and induces apoptosis in cancer cells. p38 MAPK activation leads to increased production of TNF-alpha in ischemic injury and in macrophages. However, little is known concerning the role of p38 MAPK in cisplatin-induced renal injury. Therefore, we examined the effect of cisplatin on p38 MAPK activity and the role of p38 MAPK in mediating cisplatin-induced TNF-alpha production and renal injury. In vitro, cisplatin caused a dose-dependent activation of p38 MAPK in proximal tubule cells. Inhibition of p38 MAPK activation led to inhibition of TNF-alpha production. In vivo, mice treated with a single dose of cisplatin (20 mg/kg body wt) developed severe renal dysfunction at 72 h [blood urea nitrogen (BUN): 154 +/- 34 mg/dl, creatinine: 1.4 +/- 0.4 mg/dl], which was accompanied by an increase in kidney p38 MAPK activity and an increase in infiltrating leukocytes. However, animals treated with the p38 MAPK inhibitor SKF-86002 along with cisplatin showed less renal dysfunction (BUN: 55 +/- 14 mg/dl, creatinine: 0.3 +/- 0.02 mg/dl, P < 0.05), less severe histological damage, and fewer leukocytes compared with cisplatin+vehicle-treated animals. Serum levels of TNF-alpha, sTNFRI, and sTNFRII also increased significantly in cisplatin-treated mice compared with SKF-86002-treated mice (P < 0.05). Kidney mRNA levels of TNF-alpha were significantly increased in cisplatin-treated mice compared with either SKF-86002- or saline-treated animals. The hydroxyl radical scavenger DMTU (100 mg.kg body wt(-1).day(-1)) prevented the activation of p38 MAPK by cisplatin both in vitro and in vivo. DMTU also completely prevented cisplatin-induced renal injury (BUN: 140 +/- 27 vs. 22 +/- 2 mg/dl, P < 0.005) and the increase in serum TNF-alpha (33 +/- 7 vs. 4 +/- 2 pg/ml, P < 0.005) and kidney TNF-alpha mRNA in vivo. We conclude that hydroxyl radicals, either directly or indirectly, activate p38 MAPK and that p38 MAPK plays an important role in mediating cisplatin-induced acute renal injury and inflammation, perhaps through production of TNF-alpha.
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PMID:p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. 1570 14

The role of CD40/CD154 ligation in the upregulation of genes of the proinflammatory nuclear factor-kappaB (NF-kappaB) signal transduction pathway was explored in primary cultures of human renal proximal tubule epithelial cells. Using a cDNA gene array specific for human NF-kappaB signal pathway genes, 38 genes were upregulated at 1 h, and 7 of these genes remained upregulated at 3 h. Of these genes, intercellular adhesion molecule-1 (ICAM-1) was explored in further detail. Quantitative real-time PCR for ICAM-1 mRNA expression confirmed the gene array findings. Western blot analysis and quantitative sandwich-enzyme ELISA confirmed this observation at the protein level. A cell-surface ELISA assay showed that ICAM-1 expression doubled by 48 h of CD154 exposure, and fluorescence-activated cell sorter analysis suggested that both the number of cells expressing ICAM-1 and the expression of ICAM-1 on these cells had increased. A cell adhesion assay using fluorescein-labeled human peripheral mononuclear cells showed that ICAM-1 upregulation resulted in increased mononuclear cell adhesion to the monolayer, which was abrogated by pretreatment of the monolayer with a neutralizing ICAM-1 antibody. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB-203580 but not the extracellular signal-regulated kinase 1/2 inhibitor (PD-98059) nor the protein kinase C inhibitor (calphostin) blunted ICAM-1 expression and mononuclear cell adhesion to the monolayer. We conclude that, in human renal proximal tubule epithelial cells, CD40 activation upregulates ICAM-1 (and other NF-kappaB pathway genes) expression with concomitant enhanced adhesion of mononuclear cells, which is mediated via the p38 MAPK signal transduction pathway.
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PMID:CD40/CD154 ligation induces mononuclear cell adhesion to human renal proximal tubule cells via increased ICAM-1 expression. 1571 10

Emerging clinical and experimental evidence strongly implicates proteinuria in the progression of kidney disease. One pathway involves the activation of NFkappaB by albumin, and it has been demonstrated that the activation of NFkappaB induced by albumin is dependent on mitogen-activated protein kinase ERK1/ERK2. To study the effect of albumin on gene expression, primary human renal tubular cells were exposed in vitro to albumin (1%) for 6 h, and gene expression profiling was performed with the human oligonucleotide microarray, U133A Affymetrix Gene Chip. In all, 223 genes were differentially regulated by albumin, including marked upregulation of the EGF receptor (EGFR) and IL-8. Accordingly, the authors sought to delineate the signaling pathway linking albumin to the EGFR and activation of ERK1/ERK2. It was found that albumin led to a dose- and time-dependent activation of ERK1/ERK2. Treatment with albumin led to EGFR phosphorylation, but the activation of ERK1/ERK2 was prevented by pretreatment of the cells with AG-1478, the EGFR kinase inhibitor, at a dose that inhibited EGF-induced ERK1/ERK2 activation. Exogenously administered reactive oxygen species (ROS) were found to activate ERK1/ERK2 via the EGFR and src tyrosine kinase activity and pretreatment of cells with the antioxidant N-acetylcysteine (NAC) and the NADPH oxidase inhibitor DPI abrogated albumin-induced activation of ERK1/ERK2. The src tyrosine kinase inhibitor, PP2, also inhibited the albumin-induced activation of ERK1/ERK2. Finally, pretreatment with AG-1478, the MEK inhibitor UO126, and NAC prevented the albumin-induced increase in IL-8 expression. The authors conclude that the EGF receptor plays a central role in the signaling pathway that links albumin to the activation of ERK1/ERK2 and increased expression of IL-8. Gene profiling studies suggest that there may be a positive feedback loop through the EGFR that amplifies the response of the proximal tubule cell to albumin. Taken together, these results suggest that the EGFR may be an important treatment target for kidney disease associated with proteinuria.
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PMID:Albumin activates ERK via EGF receptor in human renal epithelial cells. 1582 4

Primary cultures of renal proximal tubules are known to recapitulate several early events in the process of renal regeneration following injury. In this study, we show that suramin, a polysulfonated naphthylurea, stimulates outgrowth, scattering, and proliferation of primary cultures of renal proximal tubule cells (RPTC). These responses were comparable to those produced by epidermal growth factor (EGF). However, AG-1478 [4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline], a specific inhibitor of the EGF receptor, blocked EGF but not suramin-induced RPTC outgrowth, scattering, and proliferation. Suramin stimulated phosphorylation of Akt, a downstream kinase of phosphoinositide 3-kinase (PI3K), extracellular signaling-regulated kinase 1/2 (ERK1/2), and Src, but not the EGF receptor. Blockade of Src, but not the EGF receptor, inhibited Akt and ERK1/2 phosphorylation. Furthermore, inactivation of PI3K with LY294002 [2-(4morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] blocked suramin-induced RPTC outgrowth, scattering, and proliferation, whereas blockade of ERK1/2 had no effect. These data identify novel effects of suramin in RPTC outgrowth, scattering, and proliferation. Furthermore, suramin-induced outgrowth, scattering, and proliferation of RPTC are through Src-mediated activation of the PI3K pathway but not ERK1/2 or the EGF receptor.
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PMID:Suramin promotes proliferation and scattering of renal epithelial cells. 1583 99

Extracellular ATP plays an important role in the regulation of renal function. However, the effect of ATP on the Na(+)-glucose cotransporters (SGLTs) has not been elucidated in proximal tubule cells (PTCs). Therefore, this study was performed to examine the action of ATP on SGLTs and their related signal pathways in primary cultured rabbit renal PTCs. ATP increased [(14)C]-alpha-methyl-d-glucopyranoside (alpha-MG) uptake in a time-dependent (>1 h) and dose-dependent (>10(-6) M) manner. ATP stimulated alpha-MG uptake by increasing in V(max) without affecting K(m). ATP-induced increase of alpha-MG uptake was correlated with the increase in both SGLT1 and SGLT2 protein expression levels. ATP-induced stimulation of alpha-MG uptake was blocked by suramin (nonspecific P2 receptor antagonist), RB-2 (P2Y receptor antagonist), and MRS-2179 (P2Y(1) receptor antagonist), suggesting a role for the P2Y receptor. ATP-induced stimulation of alpha-MG uptake was blocked by pertussis toxin (PTX, a G(i) protein inhibitor), SQ-22536 (an adenylate cyclase inhibitor), and PKA inhibitor amide 14-22 (PKI). ATP also increased cAMP formation, which was blocked by PTX and RB-2. However, pretreatment of adenosine deaminase did not block ATP-induced cAMP formation. In addition, ATP-induced stimulation of alpha-MG uptake was blocked by SB-203580 (p38 MAPK inhibitor), but not by PD-98059 (p44/42 MAPK inhibitor) or SP-600125 (JNK inhibitor). Indeed, ATP induced phosphorylation of p38 MAPK. In conclusion, ATP increases alpha-MG uptake via cAMP and p38 MAPK in renal PTCs.
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PMID:ATP stimulates Na+-glucose cotransporter activity via cAMP and p38 MAPK in renal proximal tubule cells. 1601 5

Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets. Recently, we demonstrated that Hyp mice have greater urinary PGE2 levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice. To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid. We find that PGE2 production was higher in Hyp mice than in C57/B6 mice. Incubation of C57/B6 mouse renal proximal tubules with FGF-23R176Q, an active mutant form of FGR23, increased tubular PGE2 production, an effect that was inhibited by 50 microM PD-98059 and 10 microM SB-203580, inhibitors of the MAP kinase pathway. C57/B6 mice injected with FGF-23R176Q had a approximately 10-fold increase in PGE2 excretion 24 h after intraperitoneal injection of FGF-23R176Q compared with vehicle-treated controls. Finally, we show that PGE2 inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE2. In conclusion, FGF-23 increases urinary and renal tubular PGE2 production via the MAP kinase pathway and PGE2 inhibits proximal tubule phosphate transport.
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PMID:Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro. 1614 64

The most common type of renal injury in multiple myeloma is chronic tubulointerstitial nephropathy associated with casts in tubule lumens, an entity referred to as "myeloma kidney" that often progresses to end-stage kidney diseases. Myeloma kidney is associated with a significant increase in all-cause mortality, yet no effective intervention, except a limited use of steroid, is available. Here, we report that pituitary adenylate cyclase-activating polypeptide with 38 residues (PACAP38) dramatically prevents injury of cultured renal proximal tubule cells caused by myeloma light chains through suppression of proinflammatory cytokines production, by inhibiting p38 MAPK and translocation of NFkappaB via both PAC(1) and VPAC(1) receptors. The suppressive effects of PACAP was as effective as dexamethasone in all of their cytokine assays and demonstrated both in vitro and in vivo. Furthermore, PACAP38 inhibits myeloma cell growth directly and may also indirectly by suppressing production of the growth factor, IL-6, from bone marrow stromal cells, that is stimulated by adhesion of myeloma cells. These findings render PACAP38 worth evaluation as a promising candidate for an effective and safe renoprotectant in myeloma kidney, and possibly other nephropathy, and also as a new antitumor agent in multiple myeloma.
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PMID:Potential protective action of pituitary adenylate cyclase-activating polypeptide (PACAP38) on in vitro and in vivo models of myeloma kidney injury. 1620 6

Although ATP has been shown to act as a modulator in various kidney functions, its effect on renal proximal tubule cell (PTC) proliferation has not been elucidated. This study investigated the effect of ATP on cell proliferation and the effect of its related signal pathways on primary cultured PTCs. Treatment with >10(-5) M ATP for 1 h stimulated incorporation of thymidine and bromodeoxyuridine. ATP (10(-4) M)-induced stimulation of thymidine incorporation was blocked by suramin (a P2X and P2Y receptor antagonist), reactive blue 2 (a P2Y receptor antagonist), MRS-2159 (a P2X1 receptor antagonist), and MRS-2179 (a P2Y1 receptor antagonist). ATP increased intracellular Ca2+ concentration, which was blocked by suramin, methoxyverapamil, and EGTA. ATP-induced stimulation of cell proliferation was also blocked by EGTA (an extracellular Ca2+ chelator), methoxyverapamil (a Ca2+ antagonist), and nifedipine (an L-type Ca2+ channel blocker), suggesting a role for Ca2+ influx. ATP-induced phosphorylation of p38 and p44/42 MAPKs was blocked by nifedipine. ATP increased expression levels of cyclin-dependent kinase (CDK)-2, CDK-4, and cyclin E, which were blocked by suramin, reactive blue 2, MRS-2179, MRS-2159, and nifedipine. However, ATP decreased expression levels of p21WAF1/Cip1 and p27kip1. ATP-induced stimulation of thymidine incorporation and increase of CDK-2 and CDK-4 expression were blocked by SB-203580 (a p38 MAPK inhibitor) and PD-98059 (an MEK inhibitor), but not by SP-600125 (a JNK inhibitor). In conclusion, ATP stimulates proliferation by increasing intracellular Ca2+ concentration and activating p38, p44/42 MAPKs, and CDKs in PTCs.
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PMID:Role of ATP in DNA synthesis of renal proximal tubule cells: involvement of calcium, MAPKs, and CDKs. 1641 99

Although chronic exposure of renal cells to high glucose has been shown to cause cell injury, the effect of acute exposure has not been elucidated. In this study, we demonstrate that acute (10 min) exposure of human proximal tubule epithelial cells (hPTEC) to high glucose (25 mM) induces a time-dependent dual effect consisting of an early proliferation and a late apoptosis. Acute exposure of hPTEC to high glucose induced a twofold increase in DNA synthesis and cell number at 12 h. However, after 36 h, a significant decrease in cell growth is observed, followed by apoptosis. On glucose treatment, both p42/p44 mitogen-activated protein (MAP) kinases and the downstream signaling intermediate NF-kappaB were phosphorylated and translocated to the nucleus. Pretreatment of cells with MAP kinase and NF-kappaB-specific inhibitors abolished glucose-induced proliferation. However, these inhibitors were ineffective in preventing glucose-induced apoptosis. Interestingly, conditioned medium from cells exposed to high-glucose concentrations inhibited proliferation and concomitantly induced apoptosis in normal cells, suggesting that the inhibitory effect of glucose occurs through secretion of a secondary factor(s). In parallel to apoptosis, we observed an increased production of reactive oxygen species (ROS). Pretreatment of cells with the antioxidant N-acetyl cysteine reversed glucose-mediated ROS production and apoptosis, suggesting that ROS is involved in apoptosis. Our study demonstrates for the first time that a single high-glucose exposure for 10 min alone is sufficient to elicit proliferation and apoptosis in hPTEC and suggests that episodes of transient increase in glucose may contribute to cell damage leading to epithelial cell dysfunction.
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PMID:Acute effect of high glucose on long-term cell growth: a role for transient glucose increase in proximal tubule cell injury. 1646 30


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