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Campbell MT, Hile KL, Zhang H, Asanuma H, Vanderbrink BA, Rink RR, Meldrum KK: Toll-Like Receptor 4: A Novel Signaling Pathway During Renal Fibrogenesis. Am J Physiol Cell Physiol. 2008 Feb;294(2):C535-42. Epub 2007 Dec 12.
BACKGROUND: The toll-like receptor (TLR) family serves an important regulatory role in the innate immune system, and recent evidence has implicated TLR signaling in the pro-inflammatory response of a variety of endogenous and exogenous stimuli within the kidney. The role of TLR signaling in fibrotic renal injury, however, remains unknown. MATERIALS AND METHODS: C3H/HeJ TLR4 hyporesponsive mice (TLR4 (Lps-d)) or WT controls (C3H/HeOu/J) underwent either sham operation or 1 wk of unilateral ureteral obstruction (UUO). The kidneys were harvested and tissues were analyzed for TLR4 expression (Western blot; RTPCR), E-cadherin and alpha smooth muscle actin (alpha-SMA) expression (Western blot), fibroblast accumulation (fibroblast specific protein (FSP-1+) staining), renal fibrosis (collagen I RTPCR, total collagen assay, Masson's trichrome staining), cytokine gene expression (tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) RTPCR), and pSMAD2 and integrin alpha1 expression (Western blot). RESULTS: Mice with intact TLR4 signaling demonstrate a significant increase in TLR4 expression, alpha-SMA expression, fibroblast accumulation, collagen deposition, and interstitial fibrosis, and a significant decrease in E-cadherin expression in response to UUO. TLR4 deficient mice, however, exhibit a significant reduction in obstruction-induced alpha-SMA expression, fibroblast accumulation, and renal fibrosis, with preservation of E-cadherin expression. TLR4's influence on fibroblast accumulation and renal fibrosis occurred independent of any alterations in TNF-alpha, TGF-beta1, or pSMAD2 expression, but did involve alterations integrin alpha1 expression. CONCLUSION: TLR4 appears to be a significant mediator of fibrotic renal injury. While TLR4 signaling is recognized as a critical component of the innate immune response, this is the first study to demonstrate a novel role for TLR4 in renal fibroblast accumulation and tubulointerstitial fibrosis. |
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