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

Kidney Int. 2009 Sep;76(5):500-11. doi: 10.1038/ki.2009.216. Epub 2009 Jun 17.

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, alpha-smooth muscle actin and RhoA expression, fibroblast and macrophage accumulation, chemokine expression, and transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha) 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-beta1 or TNF-alpha activity. Similarly, the HK-2 cells exhibited increased alpha-smooth muscle actin expression and collagen production, and decreased E-cadherin expression in response to IL-18 stimulation without alterations in TNF-alpha or TGF-beta1 activity. Our study demonstrates that IL-18 is a significant mediator of obstruction-induced renal fibrosis and epithelial- mesenchymal transition independent of downstream TGF-beta1 or TNF-alpha production.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / analysis
  • Animals
  • Cell Line
  • Chemokines / genetics
  • Collagen / genetics
  • Collagen / metabolism
  • Epithelial Cells / pathology*
  • Fibrosis
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Interleukin-18 / physiology*
  • Kidney / pathology*
  • Macrophages / pathology
  • Male
  • Mesoderm / pathology*
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / analysis
  • Transforming Growth Factor beta1 / biosynthesis
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Actins
  • Chemokines
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-18
  • RNA, Messenger
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • alpha-smooth muscle actin, mouse
  • interleukin-18 binding protein
  • Collagen