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Macrophage metalloelastase as a major factor for glomerular injury in anti-glomerular basement membrane nephritis.

Authors: Kaneko, Y  Sakatsume, M  Xie, Y  Kuroda, T  Igashima, M  Narita, I  Gejyo, F 
Citation: Kaneko Y, etal., J Immunol 2003 Mar 15;170(6):3377-85.
Pubmed: (View Article at PubMed) PMID:12626598

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.


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RGD Object Information
RGD ID: 737630
Created: 2004-02-08
Species: All species
Last Modified: 2004-02-08
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.