Pravastatin inhibits carboxymethyllysine-induced monocyte chemoattractant protein 1 expression in podocytes via prevention of signalling events.
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) kappaB 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-kappaB and Sp1 translocation.


CONCLUSIONS
These results suggest that pravastatin prevents CML to induce MCP-1 expression in podocytes via modulation of the intracellular ERK/NF-kappaB and Sp1 signalling pathway.
Gu
Leyi
L
Renal Division, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China. guleyi@public4.sta.net.cn
Ni
Zhaohui
Z
Qian
Jiaqi
J
Tomino
Yasuhiko
Y
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015870:Gene Expression / Q000187:drug effects; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D017035:Pravastatin / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004338:Drug Combinations; C048496:N(6)-carboxymethyllysine; D008239:Lysine; D017035:Pravastatin