Activation of phosphoinositide 3-kinase in response to high glucose leads to regulation of reactive oxygen species-related nuclear factor-kappaB activation and cyclooxygenase-2 expression in mesangial cells.
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-kappaB 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-kappaB 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-kappaB activation and cyclooxygenase-2 expression and cell proliferation in mesangial cells through a phosphoinositide 3-kinase-dependent pathway.
Sheu
Meei Ling
ML
Institute of Toxicology, College of Medicine, National Taiwan University, 1, Section 1, Jen-Ai Road, Taipei, 10043, Taiwan.
Ho
Feng Ming
FM
Chao
Kuo Fang
KF
Kuo
Ming Liang
ML
Liu
Shing Hwa
SH
D019870:1-Phosphatidylinositol 4-Kinase; D000818:Animals; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology*; D005947:Glucose / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species
D019870:1-Phosphatidylinositol 4-Kinase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005947:Glucose; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; C496513:Ptgs1 protein, rat; C494920:Akt1 protein, rat