Macrophage metalloelastase as a major factor for glomerular injury in anti-glomerular basement membrane nephritis.
Rat anti-glomerular basement membrane (GBM) nephritis is a model of crescentic glomerulonephritis induced by injection of anti-GBM antiserum. To elucidate the mechanism of glomerular injury, we analyzed the gene expression patterns in the kidneys of anti-GBM nephritis rats using DNA arrays, and found that macrophage metalloelastase/matrix metalloproteinase (MMP)-12 was one of the highly expressed genes in the kidneys on days 3 and 7 after the injection of anti-GBM antiserum. Enhancement of MMP-12 mRNA expression was confirmed by Northern blot analysis, and in situ hybridization revealed that MMP-12 mRNA was expressed in ED-1-positive macrophages and multinuclear giant cells in the glomeruli with crescent. Moreover, these cells were positive with anti-rat rMMP-12 Ab on the section of the kidneys of anti-GBM nephritis rats on day 7. To clarify the role of MMP-12, we conducted a neutralization experiment using anti-rat rMMP-12 Ab, which had an ability to inhibit rMMP-12 activity of degrading natural substrate such as bovine elastin or human fibronectin in vitro. Anti-rat rMMP-12 Ab or control Ig was injected in each of six rats on days 0, 2, 4, and 6 after the injection of anti-GBM antiserum. Consequently, crescent formation and macrophage infiltration in the glomeruli were significantly reduced in the rats treated with anti-rat rMMP-12 Ab, and the amount of urine protein was also decreased. These results disclosed that MMP-12 played an important role in glomerular injury in a crescentic glomerulonephritis model, and inhibition of MMP-12 may lead to a new therapeutic strategy for this disease.
Kaneko
Yoshikatsu
Y
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences and Kidney Center, Shinraku-en Hospital, Niigata, Japan. kanekoy@med.niigata-u.ac.jp
Sakatsume
Minoru
M
Xie
Yuansheng
Y
Kuroda
Takeshi
T
Igashima
Michiko
M
Narita
Ichiei
I
Gejyo
Fumitake
F
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000201:enzymology* / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D015152:Blotting, Northern; D015153:Blotting, Western; D002465:Cell Movement / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D017403:In Situ Hybridization; D007275:Injections, Intravenous; D007678:Kidney Glomerulus / Q000201:enzymology* / Q000473:pathology*; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000009:adverse effects* / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013379:Substrate Specificity
D007106:Immune Sera; D011994:Recombinant Proteins; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12