MIP-1alpha and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis.
BACKGROUND
The precise molecular mechanisms of macrophage (Mphi) recruitment and activation in crescentic glomerulonephritis remain to be investigated. We hypothesized that locally produced macrophage inflammatory protein (MIP)-1alpha and monocyte chemoattractant protein (MCP)-1 via the chemokine receptors participate in the pathophysiology of human crescentic glomerulonephritis by recruiting and activating Mphi.


METHODS
We investigated the levels of MIP-1alpha and MCP-1 by enzyme-linked immunosorbent assay (ELISA) in 20 healthy subjects, 20 patients with crescentic glomerulonephritis, and 41 control patients with various other renal diseases. The presence of MIP-1alpha, MCP-1, and the cognate chemokine receptor for MIP-1alpha, CCR5, in the diseased kidneys was evaluated by immunohistochemical and in situ hybridization analyses.


RESULTS
MIP-1alpha-positive cells were mainly detected in crescentic lesions, whereas MCP-1 was mainly in the interstitium. In addition, we detected CCR5-positive cells in diseased glomeruli and interstitium. Urinary MIP-1alpha was detected in crescentic glomerulonephritis, even though it was below detectable levels in healthy subjects and in patients with other renal diseases without crescents. Urinary MIP-1alpha levels in the patients with crescentic glomerulonephritis were well correlated with the percentage of cellular crescents and the number of CD68-positive infiltrating cells and CCR5-positive cells in the glomeruli. However, urinary MCP-1 levels were well correlated with the percentage of both total crescents and fibrocellular/fibrous crescents and the number of CD68-positive infiltrating cells in the interstitium. Moreover, elevated urinary levels of both MIP-1alpha and MCP-1 dramatically decreased during glucocorticoid therapy-induced convalescence.


CONCLUSIONS
These observations suggest that locally produced MIP-1alpha may be involved in the development of cellular crescents in the acute phase via CCR5 and that MCP-1 may be involved mainly in the development of interstitial lesions in the chronic phase when fibrocellular/fibrous crescents are present, possibly through Mphi recruitment and activation.
Wada
T
T
First Department of Internal Medicine, School of Medicine, Kanazawa University, Japan. twada@med.kanazawa-u.ac.jp
Furuichi
K
K
Segawa-Takaeda
C
C
Shimizu
M
M
Sakai
N
N
Takeda
S I
SI
Takasawa
K
K
Kida
H
H
Kobayashi
K I
KI
Mukaida
N
N
Ohmoto
Y
Y
Matsushima
K
K
Yokoyama
H
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016375:Antisense Elements (Genetics) / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008181:Lupus Nephritis / Q000276:immunology; D008262:Macrophage Activation; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D008297:Male; D008875:Middle Aged; D019713:Receptors, CCR5 / Q000378:metabolism
D016375:Antisense Elements (Genetics); D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D005938:Glucocorticoids; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5