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- Title
Prednisolone inhibits hyperosmolarity-induced expression of MCP-1 via NF-κB in peritoneal mesothelial cells.
- Authors
Matsuo, H.; Tamura, M.; Kabashima, N.; Serino, R.; Tokunaga, M.; Shibata, T.; Matsumoto, M.; Aijima, M.; Oikawa, S.; Anai, H.; Nakashima, Y.
- Abstract
The mechanism of peritoneal fibrosis in patients on continuous ambulatory peritoneal dialysis (CAPD) is poorly elucidated. We investigated the cellular mechanism of high-glucose-induced expression of monocyte chemoattractant protein-1 (MCP-1), which is important in recruiting monocytes into the peritoneum and progression of peritoneal fibrosis, and examined the inhibitory mechanism of glucocorticoids. Rat peritoneal mesothelial cells were cultured in high-glucose-containing medium and then analyzed for phosphorylation levels of p42/44 and p38 mitogen-activated protein (MAP) kinases (MAPK), MAPK or extracellular signal-regulated kinase kinase (MEK)1/2, c-Jun N-terminal kinase (JNK)1/2, and protein kinase C (PKC) by Western blotting. Expression of MCP-1 was examined by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. DNA-binding activity of nuclear factor (NF)-κB was measured by electrophoretic mobility shift assay. High glucose increased MCP-1 mRNA and MCP-1 protein expression. Although glucose increased phosphorylation of MEK1/2, p42/44 MAPK, p38 MAPK, JNK1/2, and PKC, and DNA-binding activity of NF-κB, its effect on MCP-1 expression was suppressed only by PKC and NF-κB inhibitors. Mannitol caused a similar increase in PKC and NF-κB activation and MCP-1 synthesis. Prednisolone increased I-κB-α expression and inhibited glucose/mannitol-induced NF-κB DNA binding and MCP-1 expression without affecting PKC phosphorylation. The inhibitory effects of prednisolone on MCP-1 expression were reversed by mifepristone, a glucocorticoid receptor antagonist. Our results indicate that glucose induces MCP-1 mainly through hyperosmolarity by activating PKC and its downstream NF-κB, and that such effect was inhibited by prednisolone, suggesting the efficacy of prednisolone in preventing peritoneal fibrosis in patients on CAPD.Kidney International (2006) 69, 736–746. doi:10.1038/sj.ki.5000131; published online 11 January 2006
- Subjects
PERITONEAL dialysis; FIBROSIS; PERITONEUM; MESSENGER RNA; DNA polymerases; GLUCOSE; SUCROSE
- Publication
Kidney International, 2006, Vol 69, Issue 4, p736
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/sj.ki.5000131