Obstruction of the upper urinary tract is a major clinical problem that results in progressive, and ultimately, irreversible renal insufficiency. The majority of obstructive renal injury is attributed to progressive tubulointerstitial fibrosis and renal tubular epithelial cell damage. Interleukin 18 (IL-18) is a recently discovered pro-inflammatory cytokine that is structurally and functionally related to the IL-1 family. In humans, urinary IL-18 levels have been shown to be a sensitive and early marker of renal tubular damage from ischemic and post-transplantation ATN17, 84. Recently, circulating IL-18 levels and renal IL-18 receptor (IL-18R) expression has been shown to be elevated in patients with chronic kidney disease18, 85, 86. We therefore sought to examine IL-18's role in obstruction-induced tubulointerstitial fibrosis. Our preliminary data suggests that IL-18 stimulates obstruction-induced renal fibrosis, epithelial mesenchymal transition (EMT), and apoptotic cell death without altering downstream TNF-1 or TGF-21 activity. IL-18 was further observed to stimulate an increase in toll like receptor 4 (TLR4) expression during renal obstruction in vivo and upon direct stimulation of tubular epithelial cells in vitro, and direct antagonism of TLR4 in vitro reduced markers of IL-18-induced tubular cell injury, while direct stimulation of TLR4 increased markers of IL-18-induced tubular cell injury. We therefore hypothesize that IL-18 is a critical mediator of tubulointerstitial fibrosis and tubular epithelial cell damage during obstruction, and further, that IL-18's injurious effect is mediated through increased TLR4 expression. We will investigate this hypothesis by inducing unilateral ureteral obstruction (UUO) in genetically altered mice or by direct stimulation of tubular epithelial cells in vitro, and examine IL-18's role in obstruction-induced fibrosis, EMT, and apoptosis. We will then evaluate IL-18-induced TLR4 expression and activity as a mechanism of renal fibrosis and tubular epithelial cell damage, and finally, will evaluate STAT3's role in downstream IL-18 and TLR-4 signal transduction during UUO and its contribution to obstruction-induced fibrosis, EMT, and apoptosis. These studies will help elucidate the important role of IL-18 in obstructive renal injury and may provide a clinically relevant therapeutic strategy for the treatment of obstructive renal injury.

Public Health Relevance

Obstruction of the kidney is a major clinical problem in both children and adults that results in progressive and ultimately irreversible kidney damage. While increased expression of the inflammatory mediator, interleukin 18 (IL-18), has been demonstrated in a wide range of kidney diseases, the role of IL-18 in obstruction-induced kidney injury remains unknown. This investigation would provide novel insight into IL-18's signaling mechanisms and its role in the development of obstruction-induced kidney damage, and in turn, provide potentially clinically relevant therapeutic strategies to limit or prevent the kidney damage associated with obstruction.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Mullins, Christopher V
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Spectrum Health Hospitals
Grand Rapids
United States
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Rhee, Audrey C; Cain, Alexandra L; Hile, Karen L et al. (2013) IL-18 activation is dependent on Toll-like receptor 4 during renal obstruction. J Surg Res 183:278-84
Asanuma, Hiroshi; Vanderbrink, Brian A; Campbell, Matthew T et al. (2011) Arterially delivered mesenchymal stem cells prevent obstruction-induced renal fibrosis. J Surg Res 168:e51-9
Campbell, Matthew T; Hile, Karen L; Zhang, Hongji et al. (2011) Toll-like receptor 4: a novel signaling pathway during renal fibrogenesis. J Surg Res 168:e61-9
Bani-Hani, Ahmad H; Leslie, Jeffery A; Asanuma, Hiroshi et al. (2009) IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis. Kidney Int 76:500-11