Toll-Like Receptor 4: A Novel Signaling Pathway During Renal Fibrogenesis

• Published in: The Journal of surgical research Vol. 168; no. 1; pp. e61 - e69
• Main Authors: Campbell, Matthew T., M.D, Hile, Karen L., B.S, Zhang, Hongji, M.D, Asanuma, Hiroshi, M.D, Vanderbrink, Brian A., M.D, Rink, Richard R., M.D, Meldrum, Kirstan K., M.D
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2011
• Subjects: Animals; Cadherins - metabolism; Collagen - metabolism; Fibrosis; inflammation; kidney; Kidney - pathology; Kidney Diseases - metabolism; Kidney Diseases - pathology; Mice; Mice, Inbred C3H; Models, Animal; obstruction; S100 Calcium-Binding Protein A4; S100 Proteins - metabolism; Signal Transduction - physiology; Smad2 Protein - metabolism; Surgery; TLR4; toll-like receptor; Toll-Like Receptor 4 - metabolism; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factor-alpha - metabolism; Ureteral Obstruction - metabolism; Ureteral Obstruction - pathology; kidney; toll-like receptor; fibrosis; obstruction; inflammation; TLR4
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2009.09.053

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.