TY - JOUR
T1 - IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis
AU - Bani-Hani, Ahmad H.
AU - Leslie, Jeffery A.
AU - Asanuma, Hiroshi
AU - Dinarello, Charles A.
AU - Campbell, Matthew T.
AU - Meldrum, Daniel R.
AU - Zhang, Honji
AU - Hile, Karen
AU - Meldrum, Kirstan K.
N1 - Funding Information:
This research was supported by NIH Grants DK065892 (KK Meldrum) and GM-070628 (DR Meldrum).
PY - 2009/9
Y1 - 2009/9
N2 - 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.
AB - 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.
KW - EMT
KW - IL-18
KW - TGF-β1
KW - TNF-α
KW - Tubulointerstitial fibrosis
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U2 - 10.1038/ki.2009.216
DO - 10.1038/ki.2009.216
M3 - Article
C2 - 19536084
AN - SCOPUS:68949207806
SN - 0085-2538
VL - 76
SP - 500
EP - 511
JO - Kidney International
JF - Kidney International
IS - 5
ER -