Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species, including hydrogen peroxide (H(2)O(2)), are generated during ischemia-reperfusion and are critically involved in acute renal failure. The present studies examined the role of the extracellular signal-regulated kinase (ERK) pathway in H(2)O(2)-induced renal proximal tubular cells (RPTC) apoptosis. Exposure of RPTC to 1 mM H(2)O(2) resulted in apoptosis and activation of ERK1/2 and Akt. Pretreatment with the specific MEK inhibitors, U0126 and PD98059, or adenoviral infection with a construct that encodes a negative mutant of MEK1, protected cells against H(2)O(2)-induced apoptosis. In contrast, expression of constitutively active MEK1 enhanced H(2)O(2)-induced apoptosis. H(2)O(2) induced activation of caspase-3 and phosphorylation of histone H2B at serine 14, a posttranslational modification required for nuclear condensation, which also were blocked by ERK1/2 inhibition. Furthermore, blockade of ERK1/2 resulted in an increase in Akt phosphorylation and blockade of Akt potentiated apoptosis and diminished the protective effect conferred by ERK inhibition in H(2)O(2)-treated cells. Although Z-DEVD-FMK, a caspase-3 inhibitor, was able to inhibit histone H2B phosphorylation and apoptosis, it did not affect ERK1/2 phosphorylation. We suggest that ERK elicits apoptosis in epithelial cells by activating caspase-3 and inhibiting Akt pathways and elicits nuclear condensation through caspase-3 and histone H2B phosophorylation during oxidant injury.
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PMID:ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells. 1688 55

Although tubular necrosis in acute renal failure is associated with excessive production of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), the mechanism of ROS-induced cell necrosis remains poorly understood. In this study, we examined the role of the extracellular signaling-regulated kinase (ERK) pathway in H2O2-induced necrosis of renal proximal tubular cells (RPTC) in primary culture. Exposure of 60 to 70% confluent RPTC to 1 mM H2O2 for 3 h resulted in 44% necrotic cell death, as measured by trypan blue uptake, and inactivation of mitogen-activated protein kinase kinase (MEK), the upstream activator of ERK, by either 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126) or 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059) or overexpression of dominant-negative mutant of MEK1, inhibited cell death. In contrast, overexpression of active MEK1 enhanced H2O2-induced cell death. H2O2 treatment led to the loss of mitochondrial membrane potential (MMP) in RPTC, which was decreased by U0126 and PD98059. Furthermore, inhibition of the MEK/ERK pathway decreased oxidant-mediated ERK1/2 activation and mitochondrial swelling in isolated renal cortex mitochondria. However, treatment with cyclosporin A (CsA), a mitochondrial permeability transition blocker, did not suppress RPTC necrotic cell death, loss of MMP, and mitochondrial swelling. We suggest that ERK is a critical mediator of mitochondrial dysfunction and necrotic cell death of renal epithelial cells following oxidant injury. Oxidant-induced necrotic cell death was mediated by a CsA-insensitive loss of MMP that is regulated by the ERK pathway.
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PMID:Extracellular signal-regulated kinase activation mediates mitochondrial dysfunction and necrosis induced by hydrogen peroxide in renal proximal tubular cells. 1833 70

Rosiglitazone has been reported to exert the protective effect against acute renal failure in animal models. However, the underlying mechanisms by which it protects the damaged kidney cells are poorly understood. The present study was therefore undertaken to examine the effect of rosiglitazone on cell proliferation and to determine its molecular mechanism in opossum kidney (OK) cells, an established renal proximal tubular cell line. Rosiglitazone treatment inhibited cell proliferation in a dose- and time-dependent manner, and such effects were not associated with induction of cell death. The anti-proliferative effect of rosiglitazone was accompanied by the cell cycle arrest at the G1 phase. Western blot analysis data showed that rosiglitazone caused down-regulation of extracellular signal-regulated kinase (ERK) and Akt pathway. Transfection of constitutively active forms of MEK (an upstream kinase of ERK) and Akt prevented the proliferation inhibition induced by rosiglitazone. Rosiglitazone facilitated the recovery of cells after cisplatin-mediated injury. Taken together, these data suggest that rosiglitazone induces inhibition of cell proliferation through ERK and Akt-dependent cell cycle arrest at the G1 phase. The cell cycle arrest may play a protective role in kidney cells by preventing injured cells from progressing in the cell cycle.
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PMID:Rosiglitazone inhibits proliferation of renal proximal tubular cells via down-regulation of ERK and Akt. 2011 75