Background. A number of studies have demonstrated an important role for mac
rophages (M phi) in lipid-induced glomerular injury; however, little is kno
wn of the mechanisms that facilitate M phi infiltration in this disease. Th
is study examined the expression of M phi chemotactic molecules M phi colon
y-stimulating factor (M-CSF) and M phi migration inhibitory factor (MIF) an
d leukocyte adhesion molecules intercellular adhesion molecule-1 (ICAM-1) a
nd vascular cell adhesion molecule-1 (VCAM-1) during the induction of glome
rular M phi infiltration in ExHC rats, a strain that is susceptible to lipi
d-induced glomerular injury.
Methods. Groups of five ExHC rats were fed a high-cholesterol diet (HCD) co
ntaining 3% cholesterol, 0.6% sodium cholate, and 15% olive oil and were ki
lled after three days or one, two, or six weeks. Control animals were kille
d on day 0 or after six weeks on a normal diet.
Results. ExHC rats fed an HCD showed marked hypercholesterolemia in the abs
ence of any increase in plasma triglyceride levels from day 3 and developed
mild proteinuria and segmental glomerular lesions at week 6. Immunoperoxid
ase staining identified a significant increase in glomerular ED1(+) M phi a
t week 1. which was further increased at week 6, when M phi-derived foam ce
lls were seen in almost all glomeruli. Many of the infiltrating glomerular
M phi expressed lymphocyte function-associated antigen-1 (LFA-1) and very l
ate antigen-4 (VLA-4), which are ligands for ICAM-1 and VCAM-1, respectivel
y. Coincident with the induction of hypercholesterolemia on day 3 and prior
to significant M phi infiltration, combined in situ hybridization and immu
nohistochemistry 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 intrins
ic glomerular cells, including endothelial cells, on day 3 of the HCD.
Conclusion. These results suggest that hypercholesterolemia can induce a cl
assic proinflammatory response within the kidney glomerulus, involving prod
uction of well-described M phi chemotactic and adhesion molecules, which re
sults in M phi recruitment and the development of glomerular injury.