Abstract
Background: Up-regulation of local monocyte chemoattractant protein 1 (MCP-1) production is involved in glomerular damage through macrophage recruitment and activation in diabetic nephropathy. Advanced glycation end-products induced chemokine production in cultured mesangial cells and podocytes. Statins prevented recruitment of macrophages to the glomeruli, suggesting that statins may have the ability of anti-inflammation. In the present studies, we investigated the effects of pravastatin in the carboxymethyllysine (CML)-induced MCP-1 expression in mouse differentiated podocytes. Methods: MCP-1 gene and protein expressions were examined using RT-PCR and ELISA. Dichlorofluorescein-sensitive intracellular reactive oxygen species (ROS) generation was measured by confocal microscopy. Activation of extracellular signal-regulated kinase (ERK), nuclear factor (NF) ĸB and Sp1 were studied using Western blotting and immunocytochemistry. Results: MCP-1 was induced by CML in a time- and dose-dependent manner. CML-induced MCP-1 mRNA and protein production were inhibited by 0.1 or 1 mM pravastatin. CML rapidly generated intracellular ROS in podocytes.Pravastatin did not have any ability of blocking ROS generation. Phosphorylated ERK was found in podocytes incubated with CML and was prevented by pravastatin in a dose-dependent manner. Both Western blotting and immunocytochemistry results suggested that pretreatment of podocytes with pravastatin prevented the CML-induced NF-ĸB and Sp1 translocation. Conclusion: These results suggest that pravastatin prevents CML to induce MCP-1 expression in podocytes via modulation of the intracellular ERK/NF-ĸB and Sp1 signalling pathway.
Journal Section:
Original Paper
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