title: Toll-like receptor 4: a novel signaling pathway during renal fibrogenesis.
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.
  
  
  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 (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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Campbell
authors.forename: Karen L
authors.initials: KL
authors.lastname: Hile
authors.forename: Hongji
authors.initials: H
authors.lastname: Zhang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Brian A
authors.initials: BA
authors.lastname: Vanderbrink
authors.forename: Richard R
authors.initials: RR
authors.lastname: Rink
authors.forename: Kirstan K
authors.initials: KK
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D023421:Models, Animal; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology*
chemical_list: D015820:Cadherins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen