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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/F1065    most recent 00381.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yang, W. S. Articles by Park, S.-K. Search for Related Content PubMed PubMed Citation Articles by Yang, W. S. Articles by Park, S.-K.

High glucose-induced NF-B activation occurs via tyrosine phosphorylation of IB in human glomerular endothelial cells: involvement of Syk tyrosine kinase

Departments of ¹Internal Medicine and ³Urology, Asan Medical Center, College of Medicine, University of Ulsan, and ²Department of Internal Medicine, College of Medicine, Hallym University, Seoul, Korea

Submitted 10 August 2007 ; accepted in final form 12 March 2008

Activation of nuclear factor-B (NF-B) occurs by dissociation from IB after serine or tyrosine phosphorylation of IB, but the way of NF-B activation by high glucose has not been defined. High glucose is known to activate NF-B via protein kinase C and reactive oxygen species (ROS). In this study, we investigated how high glucose activates NF-B for CC chemokine ligand 2 production in cultured human glomerular endothelial cells. High glucose increased nuclear translocation of p65 and also increased NF-B DNA binding activity. High glucose-induced NF-B activation occurred without degradation of IB. In agreement with this, there was no increase in serine phosphorylation of IB, while tyrosine phosphorylation of IB was increased by high glucose. High glucose increased the generation of ROS, whereas both -lipoic acid and N-acetylcysteine scavenged the ROS and decreased high glucose-induced tyrosine phosphorylation of IB, nuclear translocation of p65, and NF-B DNA binding activity. Protein kinase C pseudosubstrate inhibited high glucose-induced ROS production, tyrosine phosphorylation of IB, and nuclear translocation of p65. Both BAY 61-3606, a specific inhibitor of Syk protein-tyrosine kinase, and small interfering RNA directed against Syk inhibited high glucose-induced tyrosine phosphorylation of IB as well as p65 nuclear translocation. High glucose increased tyrosine phosphorylation of Syk, while it was inhibited by -lipoic acid and protein kinase C pseudosubstrate. In summary, high glucose-induced NF-B activation occurred not by serine phosphorylation of IB. Our data suggest that ROS-mediated tyrosine phosphorylation of IB is the mechanism for high glucose-induced NF-B activation, and Syk may play a role in tyrosine phosphorylation of IB.

CC chemokine ligand 2; protein kinase C; reactive oxygen species