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:2.7.10.1 (ERK)
95,504 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 ERK-dependent phosphorylation and translocation of protein kinase Calpha (PKCalpha). On the basis of previous studies, we postulated that PTH regulates sodium pump activity through Src kinase, PLC, and calcium-dependent ERK phosphorylation. In the present work utilizing opossum kidney cells, a model of renal proximal tubule, PTH-stimulated ERK phosphorylation and membrane translocation of PKCalpha were prevented by inhibition of Src kinase, PLC, and calcium entry. Pharmacological inhibition of PLA2 did not prevent PTH-stimulated ERK phosphorylation but completely prevented PKCalpha translocation. Silencing the expression of cytosolic or calcium-independent PLA2 also prevented PTH-mediated phosphorylation of Na+-K+-ATPase alpha1-subunit and PKCalpha without blocking ERK phosphorylation. Inhibition of Na+-K+-ATPase activity by the PLA2 metabolites arachidonic acid and 20-hydroxyeicosatetraenoic acid was prevented by specific inhibition of PKCalpha but not by U0126, a MEK-1 inhibitor. Transient transfection of constitutively active MEK-1 cDNA induced phosphorylation of Na+-K+-ATPase alpha1-subunit and PKCalpha, which was prevented by PLA2 inhibition. We conclude that PTH stimulates Na+-K+-ATPase phosphorylation and decreases the activity of Na+-K+-ATPase by a sequential activation of a signaling pathway involving Src kinase, PLC, ERK, PLA2, and PKCalpha.
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PMID:PTH-mediated regulation of Na+-K+-ATPase requires Src kinase-dependent ERK phosphorylation. 1855 Jun 46

Fibroblast growth factor 23 (FGF23) is a phosphaturic factor that suppresses both sodium-dependent phosphate transport and production of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] in the proximal tubule. In vitro studies suggest that FGFR3 is the physiologically relevant receptor for FGF23 in the kidney, but this has not been established in vivo. Here, immunohistochemical analysis of the mouse kidney revealed that the proximal tubule expresses FGF receptor 3 (FGFR3) but not FGFR1, FGFR2, or FGFR4. Compared with wild-type mice, Hyp mice, which have elevated circulating levels of FGF23, exhibited low levels of serum phosphate and 1,25(OH)(2)D, reduced expression of the sodium-dependent phosphate transporter NPT2a in the proximal tubules, and low bone mineral density as a result of osteomalacia. In contrast, neither the serum phosphate nor 1,25(OH)(2)D levels were altered in FGFR3-null mice. For examination of the role of FGFR3 in mediating the effects of FGF23, Hyp mice were crossed with FGFR3-null mice; interestingly, this failed to correct the aforementioned metabolic abnormalities of Hyp mice. Ablation of FGFR4 also failed to correct hypophosphatemia in Hyp mice. Because the ablation of neither FGFR3 nor FGFR4 inhibited the renal effects of excess FGF23, the kidney localization of FGFR1 was investigated. FGFR1 co-localized with Klotho, the co-factor required for FGF23-dependent FGFR activation, in the distal tubule. In summary, neither FGFR3 nor FGFR4 is the principal mediator of FGF23 effects in the proximal tubule, and co-localization of FGFR1 and Klotho suggests that the distal tubule may be an effector site of FGF23.
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PMID:FGFR3 and FGFR4 do not mediate renal effects of FGF23. 1875 55

Impairment of proximal tubular endocytosis of glomerular-filtered proteins including albumin results in the development of proteinuria/albuminuria in patients with chronic kidney disease. However, the mechanisms regulating the proximal tubular function are largely unknown. This study aimed to investigate the role of angiotensin II type 1A receptor (AT(1A)R)- and insulin-mediated signaling pathways in regulating the expression of megalin, a multiligand endocytic receptor in proximal tubule cells (PTCs). Opossum kidney PTC-derived OK cells that stably express rat AT(1A)R but are deficient in endogenous angiotensin II receptors (AT(1A)R-OK cells) were used for this study. Treatment of the cells with angiotensin II suppressed mRNA and protein expression of megalin at 3- and 24-h incubation time points, respectively. Cellular uptake and degradation of albumin and receptor-associated protein, megalin's endocytic ligands were suppressed 24 h after angiotensin II treatment. The AT(1A)R-mediated decrease in megalin expression was partially prevented by ERK inhibitors. Insulin competed with the AT(1A)R-mediated ERK activation and decrease in megalin expression. Inhibitors of phosphatidylinositol 3-kinase (PI3K), a major component of insulin signaling, also suppressed megalin expression, and activation of the insulin receptor substrate (IRS)/PI3K system was prevented by angiotensin II. Collectively the AT(1A)R-mediated ERK signaling is involved in suppressing megalin expression in the OK cell line, and insulin competes with this pathway. Conversely, the insulin-IRS/PI3K signaling, with which angiotensin II competes, tends to stimulate megalin expression. In conclusion, there is AT(1A)R- and insulin-mediated competitive signaling cross talk to regulate megalin expression in cultured PTCs.
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PMID:Regulation of megalin expression in cultured proximal tubule cells by angiotensin II type 1A receptor- and insulin-mediated signaling cross talk. 1892 21

Fibroblast growth factor-23 (FGF23), a hormone central to phosphate and vitamin D metabolism, reduces renal absorption of phosphate by downregulating the sodium-phosphate cotransporter Npt2a. However, the mechanisms of FGF23 action in the kidney are unclear, as Npt2a localizes to the proximal tubule (PT) and the FGF23 coreceptor alpha-Klotho (KL) localizes to the distal convoluted tubule (DCT). Immunofluorescent analyses following FGF23 injection in mice showed robust staining for phospho-ERK1/2, a marker of FGF23 bioactivity, only within the DCT in a subset of KL-positive cells. This activity colocalized with the FGF23 receptor FGFR1 and was present in DCT cells that were adjacent to Npt2a-expressing PT segments. Although KL is expressed as both secreted and membrane-bound isoforms, only the membrane-bound isoform was capable of mediating FGF23 bioactivity. These findings provide novel insight into the mechanisms of hormone-regulated phosphate metabolism by identifying an intrarenal signaling axis for FGF23.
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PMID:Initial FGF23-mediated signaling occurs in the distal convoluted tubule. 1935 51

Ureteral obstruction leads to increased pressure and inducible nitric oxide synthase (iNOS) expression. This study examined the involvement of epidermal growth factor (EGF) receptor (EGFR), nuclear factor-kappaB (NFkappaB), and signal transducers and activators of transcription 3 (STAT3) in iNOS induction in human proximal tubule (HKC-8) cells in response to pressure or EGF. HKC-8 cells were subjected to 60 mmHg pressure or treated with EGF for 0-36 h. iNOS was more rapidly induced in response to EGF than pressure. The addition of EGFR, NFkappaB, and STAT3 inhibitors significantly suppressed pressure- or EGF-stimulated iNOS mRNA and protein expression. Analysis of the activated states of EGFR, NFkappaB p65, and STAT3 after exposure to both stimuli demonstrated phosphorylation within 2.5 min. Anti-EGF antibody inhibited iNOS induction in pressurized HKC-8 cells, providing evidence that endogenous EGF mediates the response to pressure. In ureteral obstruction, when pressure is elevated, phosphorylated EGFR was detected in the apical surface of the renal tubules, validating the in vitro findings. These data indicate that EGFR, NFkappaB, and STAT3 are required for human iNOS gene induction in response to pressure or EGF, indicating a similar mechanism of activation.
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PMID:Pressure activates epidermal growth factor receptor leading to the induction of iNOS via NFkappaB and STAT3 in human proximal tubule cells. 1940 42

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, -3, and -4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3(-/-) and FGFR4(-/-) null mice, and in conditional FGFR1(-/-) mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1(-/-), FGFR3(-/-), and FGFR4(-/-) mice and their wild-type counterparts. Administration of FGF23 to FGFR3(-/-) mice induced hypophosphatemia in these mice (8.0 +/- 0.4 vs. 5.4 +/- 0.3 mg/dl; p < or = 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4(-/-) mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 +/- 0.3 vs. 7.6 +/- 0.4 mg/dl; p < or = 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1(-/-) mice had no effects on serum phosphorus levels (5.6 +/- 0.3 vs. 5.2 +/- 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.
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PMID:FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. 1951 8

Triptolide, which has been used to treat inflammatory diseases, has also been reported to inhibit proliferation of cancer cells. However, it can cause severe nephrotoxicity, limiting its clinical use. Here, nephrotoxicity of triptolide was observed in vivo and in vitro. Heat shock protein 72 (HSP72) was upregulated during kidney injury in rats. HSP72 partially protected human kidney proximal tubule cell lines HK-2 and HKC from triptolide-induced injury. Phospho-Raf, phospho-MEK and phospho-ERK were elevated in HK-2 cells that overexpressed HSP72 after either heat shock or triptolide treatment, and downregulated when HSP72 was repressed by siRNA. The participation of the MEK/ERK1/2 pathway was confirmed by exposure of the cells to the MEK inhibitor U0126. Collectively, our results suggested that HSP72 plays a protective role by means of the MEK/ERK pathway, against triptolide-induced kidney injury.
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PMID:Heat shock protein 72 protects kidney proximal tubule cells from injury induced by triptolide by means of activation of the MEK/ERK pathway. 1954 56

Angiotensin II (ANG II) is taken up by proximal tubule (PT) cells via AT1 (AT1a) receptor-mediated endocytosis, but the underlying cellular mechanisms remain poorly understood. The present study tested the hypothesis that the microtubule- rather than the clathrin-dependent endocytic pathway regulates AT1-mediated uptake of ANG II and ANG II-induced sodium and hydrogen exchanger-3 (NHE-3) expression in PT cells. The expression of AT1 receptors, clathrin light (LC) and heavy chain (HC) proteins, and type 1 microtubule-associated proteins (MAPs; MAP-1A and MAP-1B) in PT cells were knocked down by their respective small interfering (si) RNAs before AT1-mediated FITC-ANG II uptake and ANG II-induced NHE-3 expression were studied. AT1 siRNAs inhibited AT1 expression and blocked ANG II-induced NHE-3 expression in PT cells, as expected (P < 0.01). Clathrin LC or HC siRNAs knocked down their respective proteins by approximately 90% with a peak response at 24 h, and blocked the clathrin-dependent uptake of Alexa Fluor 594-transferrin (P < 0.01). However, neither LC nor HC siRNAs inhibited AT1-mediated uptake of FITC-ANG II or affected ANG II-induced NHE-3 expression. MAP-1A or MAP-1B siRNAs markedly knocked down MAP-1A or MAP-1B proteins in a time-dependent manner with peak inhibitions at 48 h (>76.8%, P < 0.01). MAP protein knockdown resulted in approximately 52% decreases in AT1-mediated FITC-ANG II uptake and approximately 66% decreases in ANG II-induced NHE-3 expression (P < 0.01). These effects were associated with threefold decreases in ANG II-induced MAP kinases ERK 1/2 activation (P < 0.01), but not with altered AT1 expression or clathrin-dependent transferrin uptake. Both losartan and AT1a receptor deletion in mouse PT cells completely abolished the effects of MAP-1A knockdown on ANG II-induced NHE-3 expression and activation of MAP kinases ERK1/2. Our findings suggest that the alternative microtubule-dependent endocytic pathway, rather than the canonical clathrin-dependent pathway, plays an important role in AT1 (AT1a)-mediated uptake of extracellular ANG II and ANG II-induced NHE-3 expression in PT cells.
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PMID:AT1 receptor-mediated uptake of angiotensin II and NHE-3 expression in proximal tubule cells through a microtubule-dependent endocytic pathway. 1972 42

We previously showed that the inhalational anesthetic isoflurane protects against renal proximal tubule necrosis via isoflurane-mediated stimulation and translocation of sphingosine kinase-1 (SK1) with subsequent synthesis of sphingosine-1-phosphate (S1P) in renal proximal tubule cells (Kim M, Kim M, Kim N, D'Agati VD, Emala CW Sr, Lee HT. Am J Physiol Renal Physiol 293: F1827-F1835, 2007). We also demonstrated that the anti-necrotic and anti-inflammatory effect of isoflurane is due in part to phosphatidylserine (PS) externalization and subsequent release of transforming growth factor-beta1 (TGF-beta1) (Lee HT, Kim M, Kim J, Kim N, Emala CW. Am J Nephrol 27: 416-424, 2007). In this study, we tested the hypothesis that isoflurane, via TGF-beta1 release, increases caveolae formation in the buoyant fraction of the cell membrane of human renal proximal tubule (HK-2) cells to organize SK1 and S1P signaling. To detect SK1 protein in the caveolae/caveolin fractions, we overexpressed human SK1 in HK-2 cells (SK1-HK-2). SK1-HK-2 cells exposed to isoflurane increased caveolae/caveolin formation in the buoyant membrane fractions which contained key signaling intermediates involved in isoflurane-mediated renal tubule protection, including S1P, SK1, ERK MAPK, and TGF-beta1 receptors. Furthermore, treating SK1-HK-2 cells with recombinant TGF-beta1 or PS liposome mixture increased caveolae formation, mimicking the effects of isoflurane. Conversely, TGF-beta1-neutralizing antibody blocked the increase in caveolae formation induced by isoflurane in SK1-HK-2 cells. The increase in SK1 activity in the caveolae-enriched fractions from isoflurane-treated nonlentivirus-infected HK-2 cells, while smaller in magnitude, was qualitatively similar to that found in the SK1-HK-2 cell line. Finally, isoflurane also increased caveolae formation in the kidneys of TGF-beta1 +/+ mice but not in TGF-beta1 +/- mice (mice with reduced levels of TGF-beta1). Our study demonstrates that isoflurane organizes several key cytoprotective signaling intermediates including TGF-beta1 receptors, SK1 and ERK, within the caveolae fraction of the plasma membrane. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated renal protection and lead to new therapeutic applications of inhalational anesthetics during the perioperative period.
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PMID:Isoflurane via TGF-beta1 release increases caveolae formation and organizes sphingosine kinase signaling in renal proximal tubules. 2005 97

The phenotypes of the human renal epithelial cell lines, SK-NEP-1 and G401 (Wilm's tumour lines) and ACHN, A498, A704, Caki-1 and Caki-2 (renal adenocarcinomas), were investigated in order to develop as toxicological model systems, human renal cell lines showing properties similar to those found in discrete renal tubular segments. All cell lines, except G401, demonstrated significant (P < 0.05) stimulation of adenyl cyclase activity by calcitonin. Alkaline phosphatase activity was not detectable in any cell line except for G401. None of the cell lines tested was capable of forming epithelial layers characteristic of 'tight' epithelia. The G401 cell line displayed several characteristics of the proximal nephron including a receptor for hPTH and detectable levels of the brush-border enzymes alkaline phosphatase (0.18 +/- 0.02 mU/mg protein), leucine aminopeptidase (14.0 +/- 5.1 mU/mg protein), glutathione transferase (8.61 +/- 2.53 mU/mg protein) and gamma-glutamyl transpeptidase (24.0 +/- 2.1 mU/mg protein). hPTH (0.01-1 mum) stimulated adenyl cyclase activity in homogenates of G401 cells in a dose-dependent manner, and this stimulation was reversed by 10 mum of the specific PTH antagonist Nle, Tyr-PTH 3-34 amide. The addition of 10 mum antagonist to unstimulated G401 cell homogenate reduced the basal activity of adenyl cyclase from 87.3 +/- 17.4 to 45.9 +/- 13.2 pmol cAMP/mg protein . 15 min. The effect of known nephrotoxic agents was tested on G401 cells by measuring basic mitochondrial enzyme function (MTT assay). The antibiotic gentamicin (5 mm), significantly (P < 0.001) inhibited MTT activity in a dose-dependent manner with a maximum inhibition to23.2 +/- 9.2% of untreated G401 cells. S- (1,1,2,2,tetrafluoroethyl)- l -glutathione (4 mm) and its cysteine conjugate (2.5 mm) reduced MTT activity to 44.0 +/- 10.9% and 33.3 +/- 2.6% of control untreated G401 cells, respectively. We suggest that the G401 cell line may be a useful model of the human proximal tubule in predictive toxicology.
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PMID:Established human renal cell lines: Phenotypic characteristics define suitability for use in in vitro models for predictive toxicology. 2073 80


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