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  • Title: High glucose induces MCP-1 expression partly via tyrosine kinase-AP-1 pathway in peritoneal mesothelial cells.
    Author: Lee SK, Kim BS, Yang WS, Kim SB, Park SK, Park JS.
    Journal: Kidney Int; 2001 Jul; 60(1):55-64. PubMed ID: 11422736.
    Abstract:
    BACKGROUND: High glucose in peritoneal dialysis solutions has been implicated in the pathogenesis of peritoneal fibrosis in chronic ambulatory peritoneal dialysis (CAPD) patients. However, the mechanisms are not very clear. Peritoneal macrophages seem to participate in the process of peritoneal fibrosis and monocyte chemoattractant protein-1 (MCP-1) plays a key role in the recruitment of monocytes toward the peritoneal cavity. However, little is known about the effect of high glucose on MCP-1 expression and its signal transduction pathway in human peritoneal mesothelial cells. METHODS: Mesothelial cells were cultured with glucose (5 to 100 mmol/L) or mannitol chronically for up to seven days. MCP-1 expression of mRNA and protein was measured by Northern blot analysis and enzyme-linked immunosorbent assay (ELISA). Chemotactic activity of high-glucose-conditioned culture supernatant was measured by chemotactic assay. To examine the roles of the transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), electrophoretic mobility shift assay (EMSA) was performed. RESULTS: Glucose induced MCP-1 mRNA expression in a time- and dose-dependent manner. MCP-1 protein in cell culture supernant was also increased. Equivalent concentrations of mannitol had no significant effect. High-glucose-conditioned supernatant possessed an increased chemotactic activity for monocytes, which was neutralized by anti-MCP-1 antibody. EMSA revealed that glucose increased the AP-1 binding activity in a time- and dose-dependent manner, but not NF-kappaB. Curcumin, an inhibitor of AP-1, dose-dependently suppressed the induction of MCP-1 mRNA by high glucose. Tyrosine kinase inhibitors such as genistein (12.5 to 50 micromol/L) and herbimycin A (0.1 to 1 micromol/L) inhibited the high-glucose-induced MCP-1 mRNA expression in a dose-dependent manner, and also suppressed the high-glucose-induced AP-1 binding activity. CONCLUSIONS: : High glucose induced mesothelial MCP-1 expression partly via the tyrosine kinase-AP-1 pathway.
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