Differential regulation of matrix metalloproteinases and their inhibitors in human glomerular epithelial cells in vitro.
The present study examines the effect of transforming growth factor-beta1 (TGF-beta1) and interleukin-1beta (IL-1beta) on the regulation of gelatinase A, gelatinase B, tissue inhibitor of metalloproteinase-I (TIMP-I) and TIMP-II in human glomerular epithelial cells (GEC). The addition of TGF-beta1 resulted in the increased production and secretion of both gelatinase A (72-kD type IV collagenase) and gelatinase B (92-kD type IV collagenase), in a dose- and time-dependent manner. In contrast, the addition of IL-1beta to GEC resulted in the stimulation of secretion of gelatinase B but not gelatinase A. When the secretion of the regulatory inhibitors was examined, IL-1beta or TGF-beta1 both resulted in an increased secretion of TIMP-I, whereas the secretion of TIMP-II was downregulated. Such results demonstrate an independent and opposite regulation of the enzymes and their inhibitors. Of particular interest was the observation of the differential regulation of gelatinase A and its specific inhibitor TIMP-II (which binds to the latent form of this enzyme) in response to TGF-beta1. These results for the first time indicate that in human GEC, matrix metalloproteinases (MMP), as well as their specific inhibitors, are independently regulated by different cytokines. MMP and their regulatory tissue inhibitors (TIMP) play an important role in tissue remodeling. The results of the present study serve to emphasize both the complex regulation of matrix metabolism in the glomerulus and the potential pathologic role of an imbalance between the proteinases and their inhibitors in various forms of glomerular disease.
Martin
J
J
Institute of Nephrology, University of Wales College of Medicine, Royal Infirmary, Cardiff, United Kingdom.
Steadman
R
R
Knowlden
J
J
Williams
J
J
Davies
M
M
D001483:Base Sequence; D015415:Biomarkers / Q000032:analysis; D015152:Blotting, Northern; D002478:Cells, Cultured; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000201:enzymology; D005109:Extracellular Matrix / Q000378:metabolism*; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D053583:Interleukin-1beta; D007633:Keratins / Q000032:analysis; D007678:Kidney Glomerulus / Q000166:cytology / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D014746:Vimentin / Q000032:analysis
D015415:Biomarkers; D007375:Interleukin-1; D053583:Interleukin-1beta; D010446:Peptide Fragments; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014746:Vimentin; C052994:interleukin-1beta (163-171); D007633:Keratins; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9