https://scholars.lib.ntu.edu.tw/handle/123456789/306606
標題: | Activation of phosphoinositide 3-kinase in response to high glucose leads to regulation of reactive oxygen species-related nuclear factor-κB activation and cyclooxygenase-2 expression in mesangial cells | 作者: | SHING-HWA LIU | 公開日期: | 2004 | 卷: | 66 | 期: | 1 | 起(迄)頁: | 187-196 | 來源出版物: | Molecular Pharmacology | 摘要: | Hyperglycemia causes glomerular mesangial cell proliferation and increases matrix synthesis, contributing to early diabetic glomerulopathy. Immunohistochemical and functional correlations of renal cyclooxygenase-2 in experimental diabetes have been identified. However, the role of cyclooxygenase-2 in early diabetes-induced mesangial cell proliferation remains unknown. The authors tested the hypothesis that hyperglycemia modulates an intrarenal cyclooxygenase-2 expression, which might mediate the mesangial cell proliferation via a possible phosphoinositide 3-kinase/Akt pathway. Expression of cyclooxygenase-2, but not cyclooxygenase-1, could be induced in mesangial cells cultured under high glucose. Antioxidants (pyrrolidine dithiocarbamate and N-acetyl-L-cysteine) and phosphoinositide 3-kinase inhibitors [2-(4-morpholinyl)-8-phenyl-1(4H-benzopyran-4-one hydrochloride (LY294002) and wortmannin] effectively inhibited this high glucose-induced response. Moreover, high glucose markedly triggered the activation of phosphoinositide 3-kinase and Akt in mesangial cells, suggesting that a phosphoinositide 3-kinase/Akt pathway is involved in the high glucose-induced responses. Phosphoinositide 3-kinase inhibitors could also effectively attenuate the high glucose-triggered intracellular reactive oxygen species generation and nuclear factor-κB activation. Likewise, blocking the phosphoinositide 3-kinase or Akt activity with the dominant-negative vectors DN-p85 or DN-Akt, respectively, also greatly diminished the high glucose-triggered reactive oxygen species generation and nuclear factor-κB activation. Treatment of mesangial cells with LY294002 and cyclooxygenase-2 inhibitors [N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS398) and aspirin] effectively inhibited the high glucose-induced mesangial cell proliferation. These results suggest that high glucose may trigger the reactive oxygen species-regulated nuclear factor-κB activation and cyclooxygenase-2 expression and cell proliferation in mesangial cells through a phosphoinositide 3-kinase-dependent pathway. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-3042530936&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/306606 |
DOI: | 10.1124/mol.66.1.187 | SDG/關鍵字: | 2 morpholino 8 phenylchromone; acetylsalicylic acid; cyclooxygenase 1; cyclooxygenase 2; cyclooxygenase 2 inhibitor; glucose; immunoglobulin enhancer binding protein; n (2 cyclohexyloxy 4 nitrophenyl)methanesulfonamide; phosphatidylinositol 3 kinase; phosphatidylinositol 3 kinase inhibitor; protein kinase B; reactive oxygen metabolite; animal cell; antioxidant activity; article; attenuation; cell proliferation; controlled study; correlation analysis; diabetic nephropathy; early diagnosis; enzyme activation; enzyme analysis; enzyme mechanism; experimental diabetes mellitus; extracellular matrix; glucose blood level; hyperglycemia; immunohistochemistry; inhibition kinetics; male; mesangium; mesangium cell; mouse; nonhuman; priority journal; protein expression; rat; regulatory mechanism; 1-Phosphatidylinositol 3-Kinase; 1-Phosphatidylinositol 4-Kinase; Animals; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Enzyme Activation; Gene Expression; Glomerular Mesangium; Glucose; Isoenzymes; Male; Membrane Proteins; NF-kappa B; Prostaglandin-Endoperoxide Synthases; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species |
顯示於: | 毒理學研究所 |
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