title: Enhanced expression of membrane type-1 matrix metalloproteinase in mesangial proliferative glomerulonephritis.
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.
authors.affiliation: Department of Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: S
authors.initials: S
authors.lastname: Osada
authors.forename: K
authors.initials: K
authors.lastname: Shofuda
authors.forename: S
authors.initials: S
authors.lastname: Horikoshi
authors.forename: I
authors.initials: I
authors.lastname: Shirato
authors.forename: Y
authors.initials: Y
authors.lastname: Tomino
mesh_terms: D000818:Animals; D000961:Antilymphocyte Serum / Q000633:toxicity; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation; D004790:Enzyme Induction; D004792:Enzyme Precursors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005780:Gelatin / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D015432:Glomerulonephritis, Membranoproliferative / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D017403:In Situ Hybridization; D008297:Male; D020781:Matrix Metalloproteinase 1; D008666:Metalloendopeptidases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011507:Proteinuria / Q000209:etiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000961:Antilymphocyte Serum; D004792:Enzyme Precursors; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D005780:Gelatin; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D020781:Matrix Metalloproteinase 1