Role of high glucose-induced nuclear factor-κB activation in monocyte chemoattractant protein-1 expression by mesangial cells

Hunjoo Ha, Ra Yu Mi, Jin Choi Yoon, Masanori Kitamura, Bahl Lee Hi

Research output: Contribution to journalArticlepeer-review

264 Scopus citations

Abstract

Although high glucose (HG) has been shown to induce nuclear factor-κB (NF-κB) activation in vascular cells, the upstream regulation and the biologic significance of NF-κB activation in diabetic renal injury are not clear. It was, therefore, examined if HG-induced generation of reactive oxygen species (ROS) and protein kinase C (PKC) activation are involved in NF-κB activation in mesangial cells (MC), and the role of NF-κB activation in HG-induced monocyte chemoattractant protein-1 (MCP-1) expression by MC was further investigated. Recent observations suggest that MCP-1 may play a role in the development and progression of diabetic nephropathy. HG rapidly induced NF-κB activation in MC as estimated by electrophoretic mobility shift assay. Supershift assay suggests that most of the binding activity arose from p50/p50 and p50/p65 dimers. Antioxidants, pyrrolidine dithiocarbamate, N-acetyl-L-cystein, and trolox effectively inhibited HG-induced NF-κB activation in MC. HG rapidly generated dichlorofluorescin-sensitive intracellular ROS in MC as measured by laser-scanning confocal microscopy. HG also activated PKC rapidly in MC. Inhibition of PKC effectively blocked HG-induced intracellular ROS generation and NF-κB activation in MC. HG increased MCP-1 mRNA expression by 1.9-fold and protein secretion by 1.6-fold that of control glucose in MC transfected with control vector but not in MC transfected with dominant negative mutant inhibitor of NF-κB (IκBαM). Inhibition of either PKC or ROS effectively blocked HG-induced, but not basal, MCP-1 protein secretion by MC transfected with control vector. Thus this study demonstrates that HG rapidly activates NF-κB in MC through PKC and ROS and suggests that HG-induced NF-κB activation in MC may play a role in diabetic renal injury through upregulation of MCP-1 mRNA and protein expression.

Original languageEnglish
Pages (from-to)894-902
Number of pages9
JournalJournal of the American Society of Nephrology
Volume13
Issue number4
StatePublished - 2002

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