Up-regulation of ICAM-1 and VCAM-1 expression during macrophage recruitment in lipid induced glomerular injury in ExHC rats

Summary: A number of studies have demonstrated an important role for macrophages (Mo) in lipid induced glomerular injury; however, little is known of the mechanisms which facilitate Mo infiltration in this disease. the present study examined the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) during the development of glomerular Mo infiltration in ExHC rats; a strain which is susceptible to lipid induced glomerular injury. Twenty-five male 6 week old ExHC rats were placed on a normal diet supplemented with 3% cholesterol, 0.6% sodium cholate and 15% olive oil (high-cholesterol diet, HCD). Groups of five rats were killed prior to the beginning of the HCD or after 3 days, 1, 2 and 6 weeks on a HCD. A group of five matched ExHC rats on a normal diet served as a control. ExHC rats fed a HCD showed marked hypercholesterolaemia in the absence of any increase in plasma triglyceride levels from day 3 (190 ± 14 vs 42 ± 2 mg/dL in control; mean ± s.e.m., P<0.01), and developed mild proteinuria (21.9 ± 2.7 vs 5.2 ± 0.5 mg/24 h in control; P<0.01) and segmental glomerular lesions at week 6. Immunoperoxidase staining identified a significant increase in glomerular ED1⁺Mo at week 1 (2.0 ± 0.2 vs 1.0 ± 0.1 ED1⁺Mo/glomerular cross-section in control, P<0.01) which was further increased at week 6 (6.9 ± 0.4 ED1⁺Mo/gcs). There was also a significant increase in glomerular cells expressing the adhesion molecule ligands lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4). Coincident with Mo infiltration, there was an increase in the intensity of glomerular ICAM-1 protein expression as shown by antibody staining. In addition, northern blot analysis of cortical RNA and in situ hybridization demonstrated an increase in glomerular ICAM-1 and VCAM-1 mRNA expression from day 3 onwards. In conclusion, these results suggest that both ICAM-1/LFA-1 and VCAM-1/VLA-4 interactions play an important role in Mo recruitment and accumulation during the development of lipid induced glomerular injury.