Toll-like receptor 4: A novel signaling pathway during renal fibrogenesis

Matthew T. Campbell, Karen L. Hile, Hongji Zhang, Hiroshi Asanuma, Brian A. Vanderbrink, Richard R. Rink, Kirstan K. Meldrum

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

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 (TLR4Lps-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 (α-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-α) and transforming growth factor-beta1 (TGF-β1) RTPCR), and pSMAD2 and integrin α1 expression (Western blot). Results: Mice with intact TLR4 signaling demonstrate a significant increase in TLR4 expression, α-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 α-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-α, TGF-β1, or pSMAD2 expression, but did involve alterations integrin α1 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.

Original languageEnglish (US)
Pages (from-to)e61-e69
JournalJournal of Surgical Research
Volume168
Issue number1
DOIs
StatePublished - Jun 1 2011

Keywords

  • fibrosis
  • inflammation
  • kidney
  • obstruction
  • TLR4
  • toll-like receptor

ASJC Scopus subject areas

  • Surgery

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    Campbell, M. T., Hile, K. L., Zhang, H., Asanuma, H., Vanderbrink, B. A., Rink, R. R., & Meldrum, K. K. (2011). Toll-like receptor 4: A novel signaling pathway during renal fibrogenesis. Journal of Surgical Research, 168(1), e61-e69. https://doi.org/10.1016/j.jss.2009.09.053