Sunday, May 11, 2025
5/11/2025
IL-18 Mediates Obstruction-Induced Renal Injury via TLR4 Signaling - DESCRIPTION (provided by applicant): 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.
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