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Nitric oxide involvement in TNF-alpha and IL-1 beta-mediated changes in human mesangial cell MMP-9 and TIMP-1

Larine Nee1, Séin O'Connell, Stephen Nolan

  • 1UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.

Nephron. Experimental Nephrology
|October 1, 2008
PubMed
Abstract

Insights

Nitric oxide (NO) modulates the production of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in human mesangial cells. This finding is crucial for understanding renal disease mechanisms involving the glomerular basement membrane.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Mesangial cells secrete matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) that can degrade the glomerular basement membrane (GBM).
  • Glomerular basement membrane disruption is implicated in renal disease pathogenesis, but underlying mechanisms are not fully understood.
  • The role of nitric oxide (NO) in regulating MMP-9 and TIMP-1 production by cytokines in human mesangial cells was investigated.

Purpose of the Study:

  • To investigate the role of nitric oxide (NO) in the regulation of MMP-9 and TIMP-1 by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in human mesangial cells.
  • To elucidate the mechanisms by which NO influences cytokine-induced changes in MMP-9 and TIMP-1.

Main Methods:

  • Human mesangial cell lines (HMCL) were treated with cytokines (TNF-alpha, IL-1 beta) and nitric oxide (NO) inhibitors.
  • MMP-9 activity was assessed using gelatin zymography.
  • TIMP-1 expression was analyzed by Western blotting.
  • NO production was quantified using the Greiss assay.

Main Results:

  • Cytokine stimulation (TNF-alpha, IL-1 beta) significantly increased NO production in HMCL, mediated by inducible nitric oxide synthase (iNOS).
  • Inhibition of iNOS potentiated TNF-alpha-induced MMP-9 production and prevented cytokine-induced suppression of TIMP-1.
  • NO donors reduced basal and TNF-alpha-stimulated MMP-9 production and enhanced cytokine-induced TIMP-1 suppression.

Conclusions:

  • Nitric oxide plays a significant modulatory role in the production of MMP-9 and TIMP-1 in human mesangial cells in response to inflammatory cytokines.
  • These findings provide insights into the complex interplay between NO, cytokines, and extracellular matrix remodeling in the context of renal disease.

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