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Enhanced expression of membrane type-1 matrix metalloproteinase in mesangial proliferative glomerulonephritis
K Hayashi1, S Osada, K Shofuda
1Department of Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Abstract:
Matrix metalloproteinase-2 (MMP-2, gelatinase A) is involved in the inflammatory and sclerotic events of glomerular diseases. Newly identified membrane-type matrix metalloproteinases (MT-MMP) have been shown to activate specifically proMMP-2. To date, several types of MT-MMP have been cloned; however, their expressions in glomerular diseases have not been evaluated. To investigate the role of MT-MMP in glomerular diseases, the glomerular gene expression and enzymatic activity of MT-MMP were examined during the time course of nephritis induced in rats by anti-Thy1.1 antibody injection. Both MT1-MMP and MMP-2 mRNA expression increased prominently 5 and 10 d after anti-Thy1.1 antibody injection and decreased thereafter, as assayed by semiquantitative reverse transcription-PCR. In contrast, there were no remarkable changes in the gene expression of MT2-MMP between normal and diseased tissue, and that of MT3-MMP was not detected in isolated glomeruli by reverse transcription-PCR analysis. The activation of proMMP-2 as analyzed by gelatin zymography correlated with the glomerular MT1-MMP gene expression, suggesting that proMMP-2 was activated by MT1-MMP. Protein and mRNA expression of fibronectin, one of the major mesangial matrix proteins and substrate of MMP-2, were also synchronized with MT1-MMP and MMP-2 expression. In situ hybridization revealed intense MT1-MMP mRNA expression in the proliferating mesangial cells. Interestingly, MT1-MMP gene expression exhibited a similar distribution as alpha-smooth muscle actin expression, which was closely associated with mesangial phenotypic change. These results suggest that among the newly identified MT-MMP, MT1-MMP may play the central role in activation of proMMP-2. Furthermore, the enhancement of MT1-MMP and MMP-2 expression associated with mesangial phenotypic change may contribute to the development of anti-Thy1.1 antibody-induced glomerulonephritis and remodeling of extracellular matrices.
Insights
Membrane-type matrix metalloproteinase-1 (MT1-MMP) activates matrix metalloproteinase-2 (MMP-2) in anti-Thy1.1 antibody-induced glomerulonephritis. This MT1-MMP and MMP-2 upregulation correlates with mesangial cell changes and extracellular matrix remodeling in this kidney disease model.
Area of Science:
- Nephrology and Molecular Biology
- Extracellular Matrix Remodeling
- Glomerular Disease Pathogenesis
Background:
- Matrix metalloproteinase-2 (MMP-2) is implicated in glomerular inflammation and sclerosis.
- Newly identified membrane-type matrix metalloproteinases (MT-MMP) activate proMMP-2.
- The role of MT-MMPs in glomerular diseases remains largely unevaluated.
Purpose of the Study:
- To investigate the expression and activity of MT-MMPs in experimental glomerulonephritis.
- To determine the specific MT-MMP type involved in proMMP-2 activation.
- To correlate MT-MMP expression with mesangial matrix remodeling and phenotypic changes.
Main Methods:
- Induction of nephritis in rats using anti-Thy1.1 antibody.
- Semiquantitative reverse transcription-PCR for MT-MMP and MMP-2 mRNA.
- Gelatin zymography for MMP-2 activity.
- In situ hybridization for MT1-MMP mRNA localization.
- Analysis of fibronectin and alpha-smooth muscle actin expression.
Main Results:
- MT1-MMP and MMP-2 mRNA expression significantly increased in diseased glomeruli.
- ProMMP-2 activation correlated with MT1-MMP expression, indicating MT1-MMP as the activator.
- MT1-MMP mRNA was localized to proliferating mesangial cells, mirroring alpha-smooth muscle actin distribution.
Conclusions:
- MT1-MMP plays a key role in activating proMMP-2 in anti-Thy1.1 antibody-induced glomerulonephritis.
- Upregulation of MT1-MMP and MMP-2 is associated with mesangial cell phenotypic changes.
- These findings suggest MT1-MMP contributes to disease development and extracellular matrix remodeling in glomerulonephritis.