title: The role of Toll-like receptor 4 in high-glucose-induced inflammatory and fibrosis markers in human peritoneal mesothelial cells.
abstract: OBJECTIVE
  High glucose stimulates peritoneal inflammation and extracellular matrix accumulation in human peritoneal mesothelial cells (HPMCs). However, the roles of Toll-like receptor 4 (TLR4) and TLR2 in high-glucose-induced inflammation and fibrosis in peritoneal dialysis (PD) remain unclear. This study aimed to evaluate the effect of high glucose on TLR2 and TLR4 expression in HPMCs and to assess their impact on peritoneal inflammatory and fibrosis markers.
  
  
  METHODS
  Using cultured HPMCs, TLRs expression by high-glucose (50 mM) stimulation was assessed by quantitative real-time PCR. The association of reactive oxygen species (ROS) in high-glucose-induced TLR2 and TLR4 expression was measured by 2',7'-dichlorodihydrofluorescein diacetate staining with or without ROS inhibitor. In addition, the role of TLR2 and TLR4 on high-glucose-induced inflammatory and fibrosis markers including chemoattractant protein-1 (MCP-1), NF-κB, alpha-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-ß), and fibronectin was evaluated after inhibition of TLR2 and TLR4 by small-interfering RNA (siRNA) or anti-TLR4/TLR2 antibodies, respectively.
  
  
  RESULTS
  High glucose induced TLR1, TLR2, and TLR4 mRNAs expressions. High-glucose-induced TLR4 and TLR2 mRNAs were associated partly with the generation of ROS. Inhibition of TLR4 attenuated the high-glucose-induced expression of MCP-1 mRNA and protein, MyD88 mRNA, nuclear NF-κB p65 protein, TGF-β, fibronectin, and α-SMA mRNA and protein. However, inhibition of TLR2 did not change the expression of MCP-1 mRNA and protein.
  
  
  CONCLUSIONS
  High glucose induces inflammatory and fibrosis markers in HPMCs partly through the TLR4/MyD88/NF-κB signaling pathway rather than TLR2. Therefore, TLR4 might be a therapeutic target for ameliorating peritoneal inflammation and fibrosis in PD.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongduk Ro, Jung-gu, Daegu, 700-721, South Korea.|BK21 Plus Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, South Korea.
authors.forename: Soon-Youn
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongduk Ro, Jung-gu, Daegu, 700-721, South Korea.
authors.forename: Hye-Myung
authors.initials: HM
authors.lastname: Ryu
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongduk Ro, Jung-gu, Daegu, 700-721, South Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongduk Ro, Jung-gu, Daegu, 700-721, South Korea.
authors.forename: Jang-Hee
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongduk Ro, Jung-gu, Daegu, 700-721, South Korea.
authors.forename: Chan-Duck
authors.initials: CD
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongduk Ro, Jung-gu, Daegu, 700-721, South Korea.|BK21 Plus Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, South Korea.
authors.forename: Yong-Lim
authors.initials: YL
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongduk Ro, Jung-gu, Daegu, 700-721, South Korea. sh-park@knu.ac.kr.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Park
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010537:Peritoneum / Q000166:cytology* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D005353:Fibronectins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D005947:Glucose
keywords: Human peritoneal mesothelial cells; Peritoneal dialysis; Peritoneal fibrosis; Toll-like receptors