Clinical Investigation

Kidney International (1994) 46, 877–885; doi:10.1038/ki.1994.345

Identification and independent regulation of human mesangial cell metalloproteinases

John Martin1, Janice Knowlden1, Malcolm Davies1 and John D Williams1

1Institute of Nephrology, University of Wales College of Medicine, Cardiff Royal Infirmary, Cardiff, CF2 1SZ Wales, United Kingdom

Correspondence: Dr John D Williams, University of Wales College of Medicine, Institute of Nephrology, Cardiff Royal Infirmary, Newport Road, Cardiff CF2 1SZ Wales, United Kingdom.

Received 29 June 1993; Revised 21 April 1994; Accepted 21 April 1994.

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Abstract

Identification and independent regulation of human mesangial cell matrix 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-1beta 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.

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References

  1. Martin J, Lovett DH, Gemsa D, Sterzel RB, Davies M: Enhancement of glomerular mesangial cell neutral proteinase secretion by macrophages; role of interleukin-1. (abstract) J Immunol 137:525, 1986 | PubMed |
  2. Davies M, Thomas G, Martin J, Lovett DH: The purification and characterisation of a glomerular basement membrane-degrading proteinase from rat mesangial cell. Biochem J 251:419–425, 1988 | PubMed |
  3. Woessner JF: Martix metalloproteinases and their inhibitors in connective tissue remodelling. FASEB J 5:2145–2154, 1991 | PubMed | ISI | ChemPort |
  4. Gross J, Harper ED, Mccroskery PA, Highberger JH, Corbett C, Kang AH: Animal collagenases, specificity of action and structure of the substrate cleavage site. Biochem Biophys Res Commun 61:605–612, 1974
  5. Desrochers PE, Jeffrey JJ, Weiss SJ: Interstitial collagenase (matrix metalloproteinase-1) express serpinase activity. J Clin Invest 87:2258–2265, 1991
  6. Huhtala P, Tuuttila A, Chow LT, Lohi J, Keski-Oja J, Tryggvason K: Complete structure of the human gene for 92 kD type IV collagenase. J Biol Chem 266:16485–16490, 1991 | PubMed | ISI | ChemPort |
  7. Matrisian LM: The matrix-degrading metalloprotienases. Bioassays 14:455–463, 1992 | ChemPort |
  8. Marti H-P, Mcneil L, Davies M, Martin J, Lovett DH: Homology cloning of rat 72 kDa type IV collagenase: Cytokine and second messenger inducibility in glomerular mesangial cells. Biochem J 291:441–446, 1993
  9. Katsura M, Ito A, Hirakawa S, Mori Y: Human recombinant interleukin 1alpha increases biosynthesis of collagenase and hyaluronic acid in cultured human chorionic cells. FEBS Lett 244:315–318, 1989
  10. Salo T, Lyons JG, Rahemtulla F, Birkedal-Hansen H, Larjava H: Transforming growth factor beta1 upregulates type IV collagenase expression in cultured human keratinocytes. J Biol Chem 266:11436–11441, 1991 | PubMed | ISI | ChemPort |
  11. Salo T, Turpeeniemi-Hujanen R, Tryggvason K: Tumor-promoting esters and cell proliferation stimulate secretion of basement membrane (Type IV) collagen-degrading metalloproteinase by human fibroblasts. J Biol Chem 260:8526–8531, 1985
  12. Gutman A, Wasylyk B: The collagenase gene promoter contains a TPA and oncogene-responsive unit encompassing the PEA3 and AP-1 binding sites. EMBO J 9:2241–2246, 1990 | PubMed | ISI | ChemPort |
  13. Nicholson RC, Mader S, Nagpal S, Leid M, Rochette-Egly C, Chambon P: Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site. EMBO J 9:4443–4454, 1990 | PubMed | ISI | ChemPort |
  14. Docherty AJP, Lyons A, Smith BJ, Wright EM, Stephens PE, Harris TJR: Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 318:66–69, 1985 | Article | PubMed | ISI | ChemPort |
  15. Stetler-Stevenson WG, Brown PD, Onista M, Levy AT, Liotta LA: Tissue inhibitor of metalloproteinase-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J Biol Chem 265:13933–13938, 1990 | PubMed | ChemPort |
  16. Kleiner DE Jr, Stetler-Stevenson EG: Structural biochemistry and activation of matrix metalloproteases. Curr Opinion Cell Biol 5:891–897, 1993
  17. Wilhelm SM, Collier IE, Marmer BL, Eisen AZ, Grant GA, Goldberg GI: SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem 264:17213–17221, 1989 | PubMed | ISI | ChemPort |
  18. Collier TE, Scott MW, Eisen AZ, Marmer BL, Grant GA, Seltzer JL, Kronberger A, He C, Bauer EA, Goldberg GI: H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloproteinase capable of degrading basement membrane collagen. J Biol Chem 263:6569–6587, 1988
  19. Martin J, Davies M, Thomas G, Lovett DH: Human mesangial cells secrete a GBM-degrading neutral proteinase and a specific inhibitor. Kidney Int 36:790–801, 1989 | PubMed | ISI | ChemPort |
  20. Cawtson TE, Barrett AJ: A rapid and reproducible assay for collagenase using [1-14C] acetylated collagen. Anal Biochem 99:340–345, 1979
  21. Thomas G, Davies M, Martin J, Lovett D: A role for human mesangial cell (HMC) gelatinases in the turnover of glomerular proteoglycans. (abstract) JASN 2:583, 1991
  22. Lovett DH, Johnson RG, Marti HP, Martin J, Davies M, Couser EG: Structural characterisation of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex mediated glomerulonephritis. Am J Pathol 141:85–98, 1992 | PubMed | ISI | ChemPort |
  23. Howard EW, Bullen EC, Banda MJ: Regulation of the autoactivation of human 72 kDa progelatinase by tissue inhibitor of metalloproteinase-2. J Biol Chem 266:13064–13069, 1991
  24. Goldberg GI, Stongin A, Collier IE, Genrich LY, Marmer BL: Interaction of 92 kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with strome-lysin. J Biol Chem 267:4583–4591, 1992 | PubMed | ISI | ChemPort |
  25. Tryggvason K, Huhtala P, Tuuttila A, Chow L, Keski-Oja J, Lohi J: Structure and expression of type IV collagen genes. Differentiation and Development 32:307–312, 1990
  26. Frisch SM, Morisaki JH: Positive and negative transcriptional elements of the human type IV collagenase gene. Mol Cell Biol 10:6524–6532, 1990 | PubMed | ISI | ChemPort |
  27. Overall CM, Wrana JL, Sodek J: Transforming growth factor-beta regulation of collagenase, 72 kDa progelatinase TIMP and PA-1 expression in rat bone cell populations and human fibroblasts. Connective Tissue Res 20:289–294, 1989
  28. Lovett DH, Marti H-P, Martin J, Grond J, Kashgarian M: Transforming growth factor b1 stimulates mesangial cell synthesis of the 72 kD type IV collagenase independently of TIMP-1. (abstract) J Am Soc Nephrol 2:578, 1991
  29. Overall CM, Wrana JL, Sodek J: Transcriptional and post-tran-scriptional regulation of 72 kDa gelatinase/type IV collagenase by transforming growth factor-beta1 in human fibroblasts. J Biol Chem 266:14064–14071, 1991 | PubMed | ISI | ChemPort |
  30. Unemori EN, Hibbs MS, Amento EP: Constitutive expression of a 92 kD gelatinase (type V collagenase) by rheumatoid synovial fibroblasts and its induction in normal human fibroblasts by inflammatory cytokines. J Clin Invest 88:1656–1662, 1991 | PubMed | ChemPort |
  31. Hipps DS, Hembry RM, Docherty AJP, Reynolds JJ, Murphy G: Purification and characterisation of human 72 kDa gelatinase (Type IV collagenase). Biol Chem Hoppe-Seyler 372:287–296, 1991
  32. Wong AP, Cortez SL, Baricos WH: Role of plasmin and gelatinase in extracellular matrix degradation by cultured rat mesangial cells. Am J Physiol F1112–F1118, 1992
  33. Okada Y, Gonoji Y, Naka K, Tomita K, Nakanishi I, Iwata K, Yamashita K, Hayakawa T: Matrix metalloproteinase (92 kDa gelatinase/type IV collagenase) from HT 1080 human fibrosarcoma cells. J Biol Chem 267:21712–21719, 1992 | PubMed | ISI | ChemPort |
  34. Testa JE: Loss of metastatic phenotype by a human epidermoid carcinoma cell line, HEp-3, is accompanied by an increased expression of tissue inhibitor of metalloproteinase 2. Cancer Res 52:5597–5603, 1992

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