title: Activation of aryl hydrocarbon receptor mediates indoxyl sulfate-induced monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells.
abstract: BACKGROUND
  Indoxyl sulfate (IS) is a uremic toxin that causes renal injury, but little is known about its adverse effects on the cardiovascular system. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor that mediates adaptive and toxic responses in cells. Recent studies identified IS as an endogenous agonist for AhR, as well as other tryptophan metabolites. The aim of the study was to investigate whether IS activates AhR, with subsequent inflammatory responses contributing to the development of atherogenesis, in human umbilical vein endothelial cells (HUVECs).
  
  
  RESULTS
  We demonstrated that IS stimulates the expression of AhR target genes, including cytochromes P450 1A1 and 1B1 mRNA, in a time-dependent manner, as well as translocation of AhR into the nucleus from the cytoplasm, indicating AhR activation. IS-stimulated AhR activation was accompanied by an increase in oxidative stress, proven by enhanced NADPH oxidase 4 expression and dihydroethidium staining. Additionally, AhR inhibitors abolished the IS-induced increase in monocyte chemoattractant protein-1 (MCP-1) expression in a dose-dependent manner. Taken together, these results suggest that IS activates AhR as an endogenous agonist and induces MCP-1 expression through reactive oxygen species production in HUVECs.
  
  
  CONCLUSIONS
  Our findings give a novel understanding of the physiological effect of IS on the cardiovascular system and indicate possibilities for preventing cardiorenal syndrome by regulating serum IS levels.
authors.affiliation: Department of Laboratory Medicine, School of Medicine, Toho University, Tokyo, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Watanabe
authors.forename: Junko
authors.initials: J
authors.lastname: Tatebe
authors.forename: Shunji
authors.initials: S
authors.lastname: Namba
authors.forename: Masayuki
authors.initials: M
authors.lastname: Koizumi
authors.forename: Junichi
authors.initials: J
authors.lastname: Yamazaki
authors.forename: Toshisuke
authors.initials: T
authors.lastname: Morita
mesh_terms: D018932:Chemokine CCL2 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007200:Indican / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D013997:Time Factors
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018336:Receptors, Aryl Hydrocarbon; D007200:Indican