Mechanisms of glomerular macrophage infiltration in lipid-induced renal injury

Background. A number of studies have demonstrated an important role for macrophages (Mφ) in lipid-induced glomerular injury; however, little is known of the mechanisms that facilitate Mφ infiltration in this disease. This study examined the expression of Mφ chemotactic molecules Mφ colony-stimulating factor (M-CSF) and Mφ migration inhibitory factor (MIF) and leukocyte adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) during the induction of glomerular Mφ infiltration in ExHC rats, a strain that is susceptible to lipid-induced glomerular injury. Methods. Groups of five ExHC rats were fed a high-cholesterol diet (HCD) containing 3% cholesterol, 0.6% sodium cholate, and 15% olive oil and were killed after three days or one, two, or six weeks. Control animals were killed on day 0 or after six weeks on a normal diet. Results. ExHC rats fed an HCD showed marked hypercholesterolemia in the absence of any increase in plasma triglyceride levels from day 3 and developed mild proteinuria and segmental glomerular lesions at week 6. Immunoperoxidase staining identified a significant increase in glomerular ED¹⁺ Mφ at week 1, which was further increased at week 6, when Mφ-derived foam cells were seen in almost all glomeruli. Many of the infiltrating glomerular Mφ expressed lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4), which are ligands for ICAM-1 and VCAM-1, respectively. Coincident with the induction of hypercholesterolemia on day 3 and prior to significant Mφ infiltration, combined in situ hybridization and immunohistochemistry staining demonstrated a marked up-regulation of M-CSF and MIF mRNA expression by glomerular mesangial cells and podocytes. There was also a significant increase in ICAM-1 and VCAM-1 mRNA expression by intrinsic glomerular cells, including endothelial cells, on day 3 of the HCD. Conclusion. These results suggest that hypercholesterolemia can induce a classic proinflammatory response within the kidney glomerulus, involving production of well-described Mφ chemotactic and adhesion molecules, which results in Mφ recruitment and the development of glomerular injury.