Involvement of MCP-1 and M-CSF in glomerular foam cell formation in ExHC rats

Involvement of MCP-1 and M-CSF in hypercholesterolemia-induced glomerular foam cell formation in ExHC ratsBackgroundAn increase in glomerular macrophages (MØ) is considered a potential effector mechanism by which hyper-cholesterolemia exacerbates glomerular injury. To investigate the mechanism underlying recruitment of MØ into glomeruli, the expression of glomerular monocyte chemoattractant protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF) mRNA were examined using a lipid-induced glomer-ular injury rat model.MethodsEight-week-old male ExHC rats, a strain susceptible to hyperlipidemia, were divided into the following 4 groups: a control group (C), a high cholesterol diet group (HH), a high cholesterol diet/standard diet group (HN), which were fed a high cholesterol diet for the first 4 weeks and a standard diet for the following 4 weeks, and a probucol-treatment group (PT). Both MCP-1 and M-CSF mRNA expression in glomeruli were analyzed using the RT-PCR method. An additional experimental group (M) fed a high cholesterol diet was administered M-CSF daily for 4 weeks.ResultsThe expression of MCP-1 mRNA in glomeruli increased accompanied by an increased total serum cholesterol level in HH and HN. However, M-CSF mRNA expression was significantly suppressed at 1 or 2 weeks and gradually increased to almost basal levels. In the PT group, MCP-1 mRNA expression was suppressed. The early suppression of M-CSF mRNA expression was inhibited in PT. Renal histology showed a sig-nificant increase in foam cells in glomeruli in HH and HN rats at 4 weeks. HH rats showed increased and expanded foam cells at 8 weeks. In HN rats, however, foam cells decreased significantly after the transfer to a standard diet from a high cholesterol diet. The MCP-1 mRNA expression was suppressed after the transfer. In the PT group, foam cell formation was also suppressed. Foam cells were identified as MØ. M-CSF-treatment significantly suppressed foam cell formation in glo-meruli when compared with the untreated group levels.ConclusionThese findings suggest that hypercholesterol-emia stimulated the expression of MCP-1 in glomeruli and attracted the MØ into glomeruli. They also suggest that the reduction of hypercholesterolemia after the change in diet or treatment with probucol suppressed glomerular injury by suppressing the glomerular MCP-1 expression. M-CSF may suppress the recruitment of MØ into glomeruli and foam cell formation at an early stage of hypercholesterolemia-induced glomerular injury