Identification and independent regulation of human mesangial cell metalloproteinases.
Mesangial cells are known to secrete metalloproteinases that are capable of degrading the constituents of the GBM, and hence are potentially involved not only in the regular maintenance of the ECM components in the glomerulus, but also of contributing to any damage to these components that occurs in disease states. In this report we positively identify by Northern blotting the neutral proteinase that is constitutively secreted by the human mesangial cell (HMC) as gelatinase A (MMP2). Stimulation of HMC gelatinase by IL-1 beta or PMA causes an increase in the total amount of gelatinolytic activity secreted. On examination, however, this increased activity is shown, both by immunoreactivity and by PCR to be due to the induction of the higher molecular weight form of gelatinase, gelatinase B (MMP9), while the amount of gelatinase A remained unaffected. In addition antigen and messenger RNA have been identified for both the specific inhibitors of metalloproteinases TIMP-1 and TIMP-2. The appearance of the larger inducible gelatinase with similar substrate specificity implies that the regular turnover of matrix components may be due to the constitutively released gelatinase A while in pathological situations the inducible gelatinase B becomes predominant. The synthesis and secretion of TIMP-1 and TIMP-2 indicates that the mesangial cell is capable of controlling the activity of its own secreted enzymes.
Martin
J
J
Institute of Nephrology, University of Wales College of Medicine, Cardiff Royal Infirmary, United Kingdom.
Knowlden
J
J
Davies
M
M
Williams
J D
JD
D001483:Base Sequence; D015152:Blotting, Northern; D002478:Cells, Cultured; D017364:Collagenases / Q000032:analysis / Q000235:genetics; D017931:DNA Primers; D018093:Gelatinases / Q000032:analysis / Q000235:genetics; D005920:Glomerular Mesangium / Q000166:cytology / Q000201:enzymology*; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000032:analysis* / Q000235:genetics; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases
D017931:DNA Primers; D006023:Glycoproteins; D011506:Proteins; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9