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

• Published in: Molecular pharmacology 2004-07, Vol.66 (1), p.187
• Main Authors: Meei Ling Sheu, Feng Ming Ho, Kuo Fang Chao, Ming Liang Kuo, Shing Hwa Liu
• Format: Article
• Language: English
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.66.1.187

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(4 H )-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.