IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis

Ahmad H. Bani-Hani, Jeffery A. Leslie, Hiroshi Asanuma, Charles A. Dinarello, Matthew T. Campbell, Daniel R. Meldrum, Honji Zhang, Karen Hile, Kirstan K. Meldrum

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62 Citations (Scopus)

Abstract

Ureteral obstruction results in renal fibrosis in part due to inflammatory injury. The role of interleukin-18 (IL-18), an important mediator of inflammation, in the genesis of renal fibrosis was studied using transgenic mice overexpressing human IL-18-binding protein. In addition, HK-2 cells were analyzed following direct exposure to IL-18 compared to control media. Two weeks after ureteral obstruction, the kidneys of wild-type mice had a significant increase in IL-18 production, collagen deposition, α-smooth muscle actin and RhoA expression, fibroblast and macrophage accumulation, chemokine expression, and transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) production, whereas E-cadherin expression was simultaneously decreased. The transgenic mice with neutralized IL-18 activity exhibited significant reductions in these indicators of obstruction-induced renal fibrosis and epithelial- mesenchymal transition, without demonstrating alterations in TGF-β1 or TNF-α activity. Similarly, the HK-2 cells exhibited increased α-smooth muscle actin expression and collagen production, and decreased E-cadherin expression in response to IL-18 stimulation without alterations in TNF-α or TGF-β1 activity. Our study demonstrates that IL-18 is a significant mediator of obstruction-induced renal fibrosis and epithelial- mesenchymal transition independent of downstream TGF-β1 or TNF-α production.

Original languageEnglish
Pages (from-to)500-511
Number of pages12
JournalKidney international
Volume76
Issue number5
DOIs
Publication statusPublished - 2009 Sep 1

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Keywords

  • EMT
  • IL-18
  • TGF-β1
  • TNF-α
  • Tubulointerstitial fibrosis

ASJC Scopus subject areas

  • Nephrology

Cite this

Bani-Hani, A. H., Leslie, J. A., Asanuma, H., Dinarello, C. A., Campbell, M. T., Meldrum, D. R., Zhang, H., Hile, K., & Meldrum, K. K. (2009). IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis. Kidney international, 76(5), 500-511. https://doi.org/10.1038/ki.2009.216