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Mechanisms of glomerular macrophage infiltration in lipid-induced renal injury
M Hattori1, D J Nikolic-Paterson, K Miyazaki
1Department of Pediatric Nephrology, Tokyo Women's Medical University, School of Medicine, Japan. jq6m-httr@asahi-net.or.jp
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.
Conclusion:
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.
Insights
High cholesterol induces kidney inflammation by recruiting macrophages (M phi) through specific signaling molecules. This study reveals the molecular mechanisms driving M phi infiltration in lipid-induced glomerular injury.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Macrophages (M phi) play a crucial role in lipid-induced glomerular injury.
- Mechanisms of M phi infiltration in this condition remain poorly understood.
- This study investigates M phi migration inhibitory factor (MIF) and leukocyte adhesion molecules (ICAM-1, VCM-1) in lipid-induced glomerular injury.
Purpose of the Study:
- To examine the expression of M phi chemotactic and adhesion molecules during glomerular M phi infiltration.
- To elucidate the role of MIF, ICAM-1, and VCAM-1 in lipid-induced kidney injury.
- To understand the early molecular events leading to M phi recruitment in the glomerulus.
Main Methods:
- ExHC rats were fed a high-cholesterol diet (HCD) for varying durations.
- Analysis included immunoperoxidase staining for M phi and in situ hybridization/immunohistochemistry for mRNA expression.
- Key molecules investigated were M phi, MIF, ICAM-1, and VCAM-1.
Main Results:
- HCD induced hypercholesterolemia and mild glomerular lesions with significant M phi infiltration by week 6.
- Infiltrating M phi expressed LFA-1 and VLA-4, ligands for ICAM-1 and VCAM-1.
- MIF and M-CSF mRNA, along with ICAM-1 and VCAM-1 mRNA, were upregulated early in the HCD.
Conclusions:
- Hypercholesterolemia triggers a proinflammatory response in the kidney glomerulus.
- This involves the production of M phi chemotactic and adhesion molecules.
- These molecules mediate M phi recruitment, leading to glomerular injury.