Mechanisms of glomerular macrophage infiltration in lipid-induced renal injury.
BACKGROUND
A number of studies have demonstrated an important role for macrophages (M phi) in lipid-induced glomerular injury; however, little is known of the mechanisms that facilitate M phi infiltration in this disease. This study examined the expression of M phi chemotactic molecules M phi 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 M phi 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+ M phi at week 1, which was further increased at week 6, when M phi-derived foam cells were seen in almost all glomeruli. Many of the infiltrating glomerular M phi 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 M phi 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.


CONCLUSIONS
These results suggest that hypercholesterolemia can induce a classic proinflammatory response within the kidney glomerulus, involving production of well-described M phi chemotactic and adhesion molecules, which results in M phi recruitment and the development of glomerular injury.
Hattori
M
M
Department of Pediatric Nephrology, Tokyo Women's Medical University, School of Medicine, Japan. jq6m-httr@asahi-net.or.jp
Nikolic-Paterson
D J
DJ
Miyazaki
K
K
Isbel
N M
NM
Lan
H Y
HY
Atkins
R C
RC
Kawaguchi
H
H
Ito
K
K
D000818:Animals; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D015870:Gene Expression / Q000187:drug effects; D005921:Glomerulonephritis / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D006937:Hypercholesterolemia / Q000209:etiology / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000473:pathology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D002791:Cholesterol, Dietary; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D016173:Macrophage Colony-Stimulating Factor