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Oxidation of the Mesangial Matrix Metalloproteinase-2 Impairs Gelatinolytic Activity

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Abstract

Glomerulosclerosis is characterized by an accumulation of mesangial extracellular matrix. Oxygen radicals are strongly implicated in glomerular injury but it is unclear by what mechanism they could modulate matrix turnover dynamics. We evaluated whether oxidation of the 72 kD mesangial matrix metalloproteinase-2 (MMP-2), the major mesangial matrix-degrading enzyme, could alter its gelatinolytic activity. Oxidation of the MMP-2 using a FeCl3/ascorbate system resulted in impaired ability to degrade [3H]gelatin compared to control. Samples were also subjected to SDS-PAGE gelatin substrate zymography. At the 72 kD position a significant impairment of gelatinolytic activity of oxidized samples was observed, a decrease attenuated by coincubation of samples with the FeCl3/ascorbate system plus the radical spin trap N-tert-butyl-α-phenylnitrone suggesting specificity of oxidative changes in the decrease in enzymatic activity. These data represent the first report demonstrating that oxidation of the MMP-2 diminishes its activity and suggest a previously undescribed mechanism by which oxygen radicals may contribute to altered turnover of extracellular matrix.

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REFERENCES

  1. Diamond, J. R., J. V. Bonventre, and M. J. Karnovsky. 1986. A role for oxygen free radicals in aminonucleoside nephrosis. Kidney Int. 29:478–483.

    PubMed  Google Scholar 

  2. Baud, L., R. Ardaillou, 1986. Reactive oxygen species: production and role in the kidney. Am. J. Physiol. 251:F765–F776.

    PubMed  Google Scholar 

  3. Shah, S. V. 1988. Evidence suggesting a role for hydroxyl radical in passive Heymann nephritis in rats. Am. J. Physiol. 254:F337–F344.

    PubMed  Google Scholar 

  4. Rahman, M. A., S. S. Emancipator, and J. R. Sedor. 1988. Hydroxyl radical scavengers ameliorate proteinuria in rat immune complex glomerulonephritis. J. Lab. Clin. Med. 112:619–626.

    PubMed  Google Scholar 

  5. Diamond, J. R. 1992. The role of reactive oxygen species in animal models of glomerular disease. Am. J. Kidney Dis. 19:292–300.

    PubMed  Google Scholar 

  6. Thakur, V., P. D. Walker, and S. V. Shah. 1988. Evidence suggesting a role for hydroxyl radical in puromycin aminonucleoside-induced proteinuria. Kidney Int. 34:494–499.

    PubMed  Google Scholar 

  7. Oberle, G. P., J. Niemeyer, F. Thaiss, W. Schoeppe, and R. A. K. Stahl, 1992. Increased oxygen radical and eicosanoid formation in immune-mediated mesangial cell injury. Kidney Int. 42:69–74.

    PubMed  Google Scholar 

  8. Neale, T. J., P. P. Ojha, M. Exner, H. Poczewski, B. RÜger, J. J. Witzum, P. Davis and D. Kerjaschki, 1994. Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts of type IV collagen. J. Clin. Invest. 94:1577–1584.

    PubMed  Google Scholar 

  9. Satriano, J. A., M. Shuldiner, K. Hora, Y. Xing, Z. Shan, and D. Schlondorff. 1993. Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte colony stimulating factor, CSF-1, in response to tumor necrosis factor-α and immunoglobulin. J. Clin. Invest. 92:1564–1571.

    PubMed  Google Scholar 

  10. Oliver, C. N., B. Ahn, E. J. Moerman, S. Goldstein, and E. R. Stadtman. 1987. Age-related changes in oxidized proteins. J. Biol. Chem. 262:5488–5491.

    PubMed  Google Scholar 

  11. Oliver, C. N. 1987. Inactivation of enzymes and oxidative modification of proteins by stimulated neutrophils. Arch. Biochem. Biophys. 253:62–72.

    PubMed  Google Scholar 

  12. Mattana, J., L. Margiloff, and P. C. Singhal. 1997. Metal-catalyzed oxidation of extracellular matrix proteins disrupts integrin-mediated adhesion of mesangial cells. Biochem. Biophys. Res. Commun. 233:50–55.

    Article  PubMed  Google Scholar 

  13. Oliver, C. N., P. E. Starke-Reed, E. R. Stadtman, G. J. Liu, J. M. Carney, and R. A. Floyd. 1990. Oxidative damage to brain proteins, loss of glutamine synthetase activity and production of free radicals during ischemia/reperfusion injury to gerbil brain. Proc. Natl. Acad. Sci. U.S.A. 87:5144–5147.

    PubMed  Google Scholar 

  14. Lenz, A. G., U. Costabel, S. Shaltiel, and R. L. Levine, 1989. Determination of carbonyl groups in oxidatively modified proteins by reduction with tritiated sodium borohydride. Anal. Biochem. 177:419–425.

    PubMed  Google Scholar 

  15. Fucci, L., C. N. Oliver, M. J. Coon, and E. R. Stadtman. 1983. Inactivation of key metabolic enzymes by mixed-function oxidation reactions: possible implications in protein turnover and aging. Proc. Natl. Acad. Sci. U.S.A. 80:1521–1525.

    PubMed  Google Scholar 

  16. Rupprecht, H. D., H. O. Schocklmann, and R. B. Serzel. 1996. Cell-matrix interactions in the glomerular mesangium. Kidney Int. 49:1575–1582.

    PubMed  Google Scholar 

  17. Martin, J., J. Knowlden, M. Davies, and J. D. Williams. 1994. Identification and independent regulation of human mesangial cell metalloproteinases. Kidney Int. 46:877–885.

    PubMed  Google Scholar 

  18. Marti, H. P., L. McNeil, M. Davies, J. Martin, and D. H. Lovett. 1993. Homology cloning of rat 72 kDa type IV collagenase: cytokine and second-messenger inducibility in glomerular mesangial cells. Biochem. J. 291:441–446.

    PubMed  Google Scholar 

  19. Turck, J., A. S. Pollock, and D. H. Lovett. 1997. Gelatinase A is a glomerular mesangial cell growth and differentiation factor. Kidney Int. 51:1397–1400.

    PubMed  Google Scholar 

  20. Lovett, D. H., R. J. Johnson, H. P. Marti, J. Martin, M. Davies, and W. G. Couser. 1992. Structural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex-mediated glomerulonephritis. Am. J. Pathol. 141:85–98.

    PubMed  Google Scholar 

  21. Sorbi, D., M. Fadly, R. Hicks, S. Alexander, and L. Arbeit. 1993. Captopril inhibits the 72 kDa metalloproteinase. Kidney Int. 44:1266–1272.

    PubMed  Google Scholar 

  22. Sagar, S., D. Sorbi, L. A. Arbeit, and P. C. Singhal. 1994. Morphine modulates 72-kDa metalloproteinase Am. J. Physiol. 267:F654–F659.

    PubMed  Google Scholar 

  23. Woessner, J. F., Jr. 1991. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 5:2145–2154.

    PubMed  Google Scholar 

  24. Stadtman, E. R. 1992. Protein oxidation and aging. Science 257:1220–1224.

    PubMed  Google Scholar 

  25. Berlett, B. S., and E. R. Stadtman. 1997. Protein oxidation in aging, disease and oxidative stress. J. Biol. Chem. 272:20313–20316.

    Article  PubMed  Google Scholar 

  26. Liu, Y., R. E. Rosenthal, P. Starke-Reed, and G. Fiskum. 1993. Inhibition of postcardiac arrest brain protein oxidation by acetyl-1-carnitine. Free Rad. Biol. Med. 15:667–670.

    Article  PubMed  Google Scholar 

  27. Carney, J. M., P. E. Starke-Reed, C. N. Oliver, R. W. Landum, M. S. Cheng, J. F. Wu, and R. A. Floyd. 1991. Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-α-phenylnitrone. Proc. Natl. Acad. Sci. U.S.A. 88:3633–3636.

    PubMed  Google Scholar 

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Mattana, J., Margiloff, L., Sharma, P. et al. Oxidation of the Mesangial Matrix Metalloproteinase-2 Impairs Gelatinolytic Activity. Inflammation 22, 269–276 (1998). https://doi.org/10.1023/A:1022396015294

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