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Involvement of MCP-1 and M-CSF in glomerular foam cell formation in ExHC rats
1Third Department of Internal Medicine, Wakayama Medical College, Japan.
Background:
An increase in glomerular macrophages (MO) is considered a potential effector mechanism by which hypercholesterolemia exacerbates glomerular injury. To investigate the mechanism underlying recruitment of MO 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 glomerular injury rat model.
Methods:
Eight-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.
Results:
The 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 significant 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 MO. M-CSF-treatment significantly suppressed foam cell formation in glomeruli when compared with the untreated group levels.
Conclusion:
These findings suggest that hypercholesterolemia stimulated the expression of MCP-1 in glomeruli and attracted the MO 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 MO into glomeruli and foam cell formation at an early stage of hypercholesterolemia-induced glomerular injury.
Insights
High cholesterol increases glomerular macrophages (MO) by stimulating monocyte chemoattractant protein-1 (MCP-1) expression. Reducing cholesterol or using probucol suppresses this, while macrophage colony-stimulating factor (M-CSF) may inhibit MO recruitment.
Area of Science:
- Nephrology
- Cardiovascular Research
- Immunology
Background:
- Hypercholesterolemia is linked to increased glomerular macrophages (MO), a key factor in exacerbating kidney injury.
- The mechanisms of MO recruitment into glomeruli during hypercholesterolemia require further investigation.
- Understanding these pathways is crucial for developing targeted therapies for cholesterol-induced kidney damage.
Purpose of the Study:
- To investigate the role of monocyte chemoattractant protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF) mRNA expression in MO recruitment during hypercholesterolemia-induced glomerular injury.
- To examine the effects of dietary cholesterol reduction and probucol treatment on these molecular pathways and subsequent kidney pathology.
- To explore the potential protective role of M-CSF in early-stage hypercholesterolemic nephropathy.
Main Methods:
- Utilized a rat model of hyperlipidemia (ExHC rats) with four experimental groups: control, high cholesterol diet, high cholesterol/standard diet switch, and probucol treatment.
- Quantified glomerular MCP-1 and M-CSF mRNA expression using RT-PCR.
- Assessed renal histology for foam cell accumulation and identified foam cells as MO.
Main Results:
- High cholesterol diet significantly increased glomerular MCP-1 mRNA expression and foam cell accumulation.
- Dietary cholesterol reduction and probucol treatment suppressed MCP-1 expression and reduced foam cells.
- M-CSF mRNA expression was initially suppressed by hypercholesterolemia but M-CSF administration showed a trend towards suppressing foam cell formation.
Conclusions:
- Hypercholesterolemia promotes glomerular MO infiltration via increased MCP-1 expression, contributing to kidney injury.
- Lowering cholesterol levels or using probucol mitigates glomerular injury by reducing MCP-1 expression.
- M-CSF may play a protective role by suppressing MO recruitment and foam cell formation in early hypercholesterolemic kidney disease.