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

We previously demonstrated that light chain (LC) endocytosis by human proximal tubule cells (PTCs) leads to production of cytokines through activation of NF-kappaB. Here, we examined the role of MAPK pathways in these responses using four species of myeloma LCs (kappa(1), kappa(2), kappa(3), and lambda(1)) previously shown to induce cytokine production by PTCs. Among these, kappa(1)-LC, which yielded the strongest cytokine responses, was selected for detailed studies. Activation of MAPKs was probed by Western blot analysis for the active kinases, ERK 1/2, JNK 1/2, and p38 in kappa(1)-LC-exposed human PTCs. To evaluate the functional role of MAPKs in LC-induced cytokine responses, we tested the effects of U-0126, an ERK inhibitor; SP-600125, an inhibitor of JNK; SB-203580, a p38 inhibitor; and curcumin, a JNK-AP-1 inhibitor, all added to media before 4-h exposure to 1.5 mg/ml kappa(1)-LC. IL-6 and monocyte chemotactic protein-1 (MCP-1) were determined by ELISA. Both LC and human serum albumin (HSA) activated ERK, although the HSA effect was weaker. kappa(1)-LC stimulated all three MAPKs, although phosphorylation of ERK was more pronounced and sustained than others. Inhibitors of ERK, JNK, and p38 reduced LC-induced IL-6 and MCP-1 production. These findings suggest that activation of MAPKs plays a role in LC-induced cytokine responses in PTCs. Activation of MAPKs may be involved in cytokine responses induced by other proteins as well as LCs and may be pivotal in the pathophysiology of tubulointerstitial injury in proteinuric diseases.
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PMID:Role of MAPK pathways in light chain-induced cytokine production in human proximal tubule cells. 1258 6

Aquaporin-1 (AQP1) is a water channel that is induced by hypertonicity. The present study was undertaken to clarify the osmoregulation mechanism of AQP1 in renal medullary cells. In cultured mouse medullary (mIMCD-3) cells, AQP1 expression was significantly induced by hypertonic treatment with impermeable solutes, whereas urea had no effect on AQP1 expression. This result indicates the requirement of a hypertonic gradient. Hypertonicity activated ERK, p38 kinase, and JNK in mIMCD-3 cells. Furthermore, all three MAPKs were phosphorylated by the upstream activation of MEK1/2, MKK3/6, and MKK4, respectively. The treatments with MEK inhibitor U0126, p38 kinase inhibitor SB203580, and JNK inhibitor SP600125 significantly attenuated hypertonicity-induced AQP1 expression in mIMCD-3 cells. In addition, hypertonicity-induced AQP1 expression was significantly reduced by both the dominant-negative mutants of JNK1- and JNK2-expressing mIMCD-3 cells. NaCl-inducible activity of AQP1 promoter, which contains a hypertonicity response element, was attenuated in the presence of U0126, SB203580, and SP600125 in a dose-dependent manner and was also significantly reduced by the dominant-negative mutants of JNK1 and JNK2. These data demonstrate that the activation of ERK, p38 kinase, and JNK pathways and the hypertonicity response element in the AQP1 promoter are involved in hypertonicity-induced AQP1 expression in mIMCD-3 cells.
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PMID:Hypertonicity-induced aquaporin-1 (AQP1) expression is mediated by the activation of MAPK pathways and hypertonicity-responsive element in the AQP1 gene. 1260 Sep 99

Reabsorption of phosphate in the proximal tubule is mainly mediated by the type IIa Na(+)/P(i) cotransporter (NaPi-IIa) and tightly regulated by a variety of factors including dietary phosphate intake and parathyroid hormone (PTH). PTH signals through both apical and basolateral PTH receptors and induces the rapid internalization and subsequent degradation of NaPi-IIa. At least two signalling cascades can be activated by PTH: the PLC/PKC and the cAMP/PKA pathways. Recent evidence from OK cell culture suggested the involvement of MAPK kinases in the PTH action. Here we used freshly isolated coronal mouse kidney slices and incubated them in a physiological buffer in the absence and presence of PTH with inhibitors and activators of the various signalling cascades to further study the events leading to internalization of NaPi-IIa. No alterations in the pattern of immunostaining for alpha-tubulin, actin and several brush border membrane proteins demonstrated intactness of the slices over the experimental period. Application of PTH (100 nM) induced a strong decrease of NaPi-IIa brush border staining and internalization after 45 min of incubation. The localization of the Na(+)/sulphate cotransporter (NaSi), however, was not affected. The internalization of NaPi-IIa could be completely prevented by the PKC inhibitor chelerythrine (1 micro M) or the MAPK-kinase (ERK1/2) inhibitor PD098059 (20 micro M). Without PTH both inhibitors alone had no effect. PTH induced phosphorylation of the ERK1/2 MAPK-kinases which was prevented by PD 098059. Separate activation of the cAMP/PKA pathway by 8-Br-cAMP was completely prevented by PD098059 whereas activation of the PLC/PKC pathway by the PKC activator 1,2-dioctanoyl-sn-glycerol (DOG) and the PKG pathway by 8-Br-cGMP induced internalization of NaPi-IIa which could be only partly blocked by PD 098059. Inhibition by SB203580 or activation by anisomycin of the p38 kinase pathway had no influence on NaPi-IIa localization under control conditions or after PTH stimulation. Furthermore, the PTH-induced decrease in NaPi-IIa protein could be reduced by PD 098059. These results suggest that the ERK1/2 MAPK kinase pathway plays a central role in the signalling of PTH leading to specific internalization and subsequent degradation of the type II NaPi-IIa cotransporter in the proximal tubule.
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PMID:Involvement of the MAPK-kinase pathway in the PTH-mediated regulation of the proximal tubule type IIa Na+/Pi cotransporter in mouse kidney. 1269 Apr 63

Endogenous cardiotonic steroids (ECS) are putative ligands of the inhibitory binding site of the membrane sodium pump (Na+, K+-ATPase). There is growing evidence that cardiotonic steroids may promote the growth of cardiac and vascular myocytes, including evidence indicating growth stimulation at concentrations in the same range as circulating ECS concentrations. We investigated four parameters to determine whether ouabain, a proposed ECS, promotes growth of immortalized rat proximal tubule epithelial cells: cell count by hemocytometer; metabolic activity as reflected in the mitochondrial conversion of the tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, to its formazan product (MA); DNA synthesis reflected as bromodeoxyuridine incorporation (DNA); and mitosis reflected as histone phosphorylation state detected using anti-phosphohistone 3 antibody (HP). Maximum stimulatory responses were observed at 1 nm ouabain (MA, 20.3% increase, p < 0.01; DNA, 28.4% increase, p < 0.001; HP, maximum response at 0.5 h, 50% increase, p < 0.001). We observed that growth stimulation was associated with stimulation of ERK1/2 phosphorylation (ERK-P), and both growth and ERK-P could be blocked by the MEK inhibitor (U0126, 100 nm). Western blot analysis revealed that the only alpha isoform of Na+, K+-ATPase that could be detected in these cultures was the highly ouabain-resistant alpha1 isoform. Measurement of ouabain inhibition of ion transport in these cultures using 86Rb+ uptake revealed the predominance of the expected ouabain-resistant isoform (IC50 = 24 microm) and an additional minor ( approximately 15%) ouabain-sensitive inhibition with IC50 approximately 30 pm. Similar bimodal transport inhibition curves were obtained in freshly dissected rat proximal tubules. These results indicate that renal epithelial cells may be a sensitive target of the ERK1/2-activating and growth-promoting effects of ouabain even in the presence of ouabain-resistant Na+, K+-ATPase.
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PMID:Ouabain is a potent promoter of growth and activator of ERK1/2 in ouabain-resistant rat renal epithelial cells. 1273 49

Cisplatin remains a major antineoplastic drug for the treatment of solid tumors. Its chief dose-limiting side effect is nephrotoxicity, which evolves slowly and predictably after initial and repeated exposure. The kidney accumulates cisplatin to a higher degree than other organs perhaps via mediated transport. Functionally, reduced renal perfusion and a concentrating defect characterize its nephrotoxicity, whereas morphologically necrosis of the terminal portion of the proximal tubule and apoptosis predominantly in the distal nephron characterize its effects on cell fate. Among the earliest reactions of the kidney to cisplatin is the activation of the MAPK cascade and molecular responses typical of the stress response. Repression of genes characteristic of the mature phenotype of the kidney, especially those serving transport function of the kidney, is also prominent. Metabolic responses, cell cycle events and the inflammatory cascade seem to be important determinants of the degree of renal failure induced by cisplatin. Manipulation of these responses may be exploited to reduce its toxicity clinically.
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PMID:Cisplatin nephrotoxicity. 1368 May 35

ANG II and Na+-glucose cotransporter have been reported to be associated with the onset of diverse renal diseases. However, the effect of ANG II on Na+-glucose cotransporter activity was not elucidated. The effects of ANG II on alpha-methyl-D-[14C]glucopyranoside (alpha-MG) uptake and its related signal pathways were examined in the primary cultured rabbit renal proximal tubule cells (PTCs). ANG II (>2 h; >10(-9) M) inhibited alpha-MG uptake in a time- and concentration-dependent manner and decreased the protein level of Na+-glucose cotransporters, the expression of which was abrogated by both actinomycin D and cycloheximide exposure. ANG II-induced inhibition of alpha-MG uptake was blocked by losartan, an ANG II type 1 (AT1) receptor blocker, but not by PD-123319, an ANG II type 2 receptor blocker. ANG II-induced inhibition of alpha-MG uptake was blocked by genistein, herbimycin A [tyrosine kinase (TK) inhibitors], mepacrine, and AACOCF3 (phospholipase A2 inhibitors), suggesting the role of TK phosphorylation and arachidonic acid (AA). Indeed, ANG II increased AA release, which was blocked by losartan or TK inhibitors. The effects of ANG II on AA release and alpha-MG uptake also were abolished by staurosporine and bisindolylmaleimide I (protein kinase C inhibitors) or PD-98059 (p44/42 MAPK inhibitor), but not SB-203580 (p38 MAPK inhibitor), respectively. Indeed, ANG II increased p44/42 MAPK activity. ANG II-induced activation of p44/42 MAPK was blocked by staurosporine. In conclusion, ANG II inhibited alpha-MG uptake via PKC-MAPK-cPLA2 signal cascade through the AT1 receptor in the PTCs.
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PMID:Signaling cascade of ANG II-induced inhibition of alpha-MG uptake in renal proximal tubule cells. 1464 48

We recently showed that, in a proximal tubule cell line (opossum kidney cells), epithelial growth factor (EGF) stimulates basolateral organic anion transport (OAT) via ERK1/2, arachidonic acid, phospholipase A2, and generation of prostaglandins. PGE2 binds the prostanoid receptor and, thus, activates adenylate cyclase and PKA, which stimulate basolateral organic anion uptake. In the present study, we investigated whether this regulatory cascade is also true 1) for ex vivo conditions in isolated renal proximal (S2) tubules from rabbit and 2) in a human renal epithelial cell line stably expressing human OAT1 (IHKE-hOAT1). EGF activated ERK1/2 in S2 tubules and IHKE-hOAT1, and, in both cases, inhibition of ERK activation (by U-0126) abolished this stimulation. In S2 tubules and IHKE-hOAT1, EGF led to an increase of organic anion uptake, which again was inhibited by U-0126. PGE2 stimulated basolateral organic anion uptake in rabbit S2 tubules and IHKE-hOAT1. EGF- and PGE2-mediated stimulation of organic anion uptake was abolished by inhibition of PKA in rabbit S2 tubules and IHKE-hOAT1, respectively. We conclude that 1) stimulation of basolateral organic anion uptake by EGF or PGE2 is a widespread (if not general) regulatory mechanism, 2) the signal transduction pathway involved seems to be general, 3) stimulation of basolateral organic anion uptake by EGF or PGE2 is also present under ex vivo conditions and, thus, is not a cell culture artifact, 4) activation of OAT1 is sufficient to explain the stimulatory effects of EGF and PGE2 in opossum kidney cells and rabbit S2 segments, and 5) stimulation of basolateral OAT1 by EGF or PGE2 is also important in humans and, thus, may have clinical implications.
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PMID:Action of EGF and PGE2 on basolateral organic anion uptake in rabbit proximal renal tubules and hOAT1 expressed in human kidney epithelial cells. 1464 51

The role of caveolae in CD40/CD154 activation of proinflammatory chemokines and their potential role in renal inflammatory disease were explored in primary cultures of human renal proximal tubule epithelial cells. With the use of a cell fractionation assay, caveolin-1 (Cav-1), the defining structural protein of caveolae, was detected exclusively in the cell membrane (detergent insoluble) component of resting and CD40-activated cells. In the unstimulated condition, CD40 was associated with Cav-1, and with activation of the receptor by its cognate ligand CD154, CD40 disassociated from Cav-1. Other previously identified components of the CD40 signaling pathway, namely, SAPK/JNK, p38, and ERK1/2 MAPKs, but not tumor necrosis factor receptor-associated factor 6 (TRAF-6), were also present within caveolae and dissociated from this structure with ligation of the CD40 receptor. Disruption of caveolae with filipin diminished CD40-mediated MAPK activation and blunted downstream monocyte chemoattractant protein-1 (MCP-1) and IL-8 production. Similarly, dislodgment of signaling proteins from their scaffolding with a peptide targeted to the Cav-1 scaffolding domain (CSD) resulted in blunted MAPK activation and augmented IL-8 and MCP-1 production. In contrast, epidermal growth factor (EGF)-mediated tyrosine phosphorylation of the EGF receptor and activation of ERK1/2 were not interrupted by the peptide. We conclude that in human renal proximal tubule epithelial cells, CD40 and its downstream MAPK signaling proteins are located in membrane rafts and that disruption of caveolae or dislodgment of signaling proteins from the CSD diminishes MAPK activation and IL-8 and MCP-1 production in these cells.
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PMID:Functional caveolae are a prerequisite for CD40 signaling in human renal proximal tubule cells. 1466 33

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


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