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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 
 

Role of receptor for advanced glycation end-products and signalling events in advanced glycation end-product-induced monocyte chemoattractant protein-1 expression in differentiated mouse podocytes.

BACKGROUND: Upregulation of local monocyte chemoattractant protein-1 (MCP-1) production is involved in glomerular damage through macrophage recruitment and activation in diabetic nephropathy. Treatment of db/db mice with soluble receptor for advanced glycation end-products (RAGE) prevented recruitment of macrophages to the glomeruli and reduced albuminuria, suggesting that binding of ligands and RAGE may be involved in MCP-1 expression. Therefore, we investigated the role of advanced glycation end-products (AGEs) in MCP-1 production by podocytes and signalling events after RAGE activation. METHODS: MCP-1 gene and protein expression were examined by using reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay in differentiated mouse podocytes. Dichlorofluorescein-sensitive intracellular reactive oxygen species (ROS) generation was measured by confocal microscopy. RAGE, phosphorylation of mitogen-activated protein kinases, nuclear factor (NF)-kappaB, c-Jun and Sp1 were studied using western blotting and immunocytochemistry. RESULTS: Both differentiated and undifferentiated podocytes expressed RAGE. MCP-1 was induced by AGEs and carboxymethyllysine (CML) in a time-dependent and dose-dependent manner in differentiated podocytes. Neutralizing antibody for RAGE suppressed AGE- and CML-induced MCP-1 production. AGEs and CML rapidly generated intracellular ROS in podocytes. Blocking of ROS by using N-acetyl-l-cysteine abolished CML and H(2)O(2)-induced MCP-1 expression. Phosphorylated extracellular signal-regulated kinase ( ERK) was found in podocytes incubated with CML and was prevented by N-acetyl-l-cysteine or 7'-amino 4 [trifluoromethyl]. PD98059, an inhibitor of ERK, partially prevented CML-induced MCP-1 gene expression. NF-kappaB and Sp1 were translocated into the nucleus after podocytes were incubated with CML for 60 min. Parthenolide and mithramycin A, inhibitors of NF-kappaB and Sp1, respectively, abolished CML-induced MCP-1 gene expression in a dose-dependent manner. CONCLUSIONS: These results suggest that AGEs and CML induce MCP-1 expression in podocytes through activation of RAGE and generation of intracellular ROS. NF-kappaB and Sp1 regulate MCP-1 gene transcription.[1]

References

  1. Role of receptor for advanced glycation end-products and signalling events in advanced glycation end-product-induced monocyte chemoattractant protein-1 expression in differentiated mouse podocytes. Gu, L., Hagiwara, S., Fan, Q., Tanimoto, M., Kobata, M., Yamashita, M., Nishitani, T., Gohda, T., Ni, Z., Qian, J., Horikoshi, S., Tomino, Y. Nephrol. Dial. Transplant. (2006) [Pubmed]
 
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