title: A uremic solute, P-cresol, inhibits the proliferation of endothelial progenitor cells via the p38 pathway.
abstract: BACKGROUND
  Endothelial dysfunction is a consistent finding in uremic patients. Whether the uremic solutes, p-cresol and indoxyl sulfate, affect the cellular function of endothelial progenitor cells (EPCs) was tested.
  
  
  RESULTS
  EPCs were isolated from healthy adults and treated with p-cresol (10-80 μg/ml) or indoxyl sulfate (25-200 μg/ml) with ranges of concentration similar to those found in uremic patients. The effect of p-cresol or indoxyl sulfate on the viability of EPCs was examined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In vitro angiogenesis of EPCs was tested by a matrigel assay. Signal pathways activated by these solutes were also studied. The viability of EPCs was dose- and time- dependently inhibited by p-cresol and indoxyl sulfate, respectively (both P < 0.05). The angiogenesis capacity of EPCs was suppressed significantly by p-cresol but not by indoxyl sulfate. Phosphorylated p38 and Erk1/2 was increased by p-cresol, while P38 inhibitor SB203580 reversed the effect of p-cresol in the MTT assay. Notably, a dose of 80 μg/ml p-cresol decreased the Notch1 intracellular domain level in EPCs.
  
  
  CONCLUSIONS
  This study has demonstrated that p-cresol inhibits proliferation of EPCs via activation of p38 MAPK pathways. P-cresol also attenuates angiogenesis function of EPCs and interferes with the Notch1 path-way.
authors: Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Yuan
authors: Y
authors: Ying
authors: Ke
authors: K
authors: Yang
authors: Yan
authors: Y
authors: Liu
authors: Qiu J
authors: QJ
authors: Chen
authors: Wei F
authors: WF
authors: Shen
authors: Lin
authors: L
authors: Lu
authors: Rui Y
authors: RY
authors: Zhang
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003408:Cresols / Q000737:chemistry / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*; D014556:Urine / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D003408:Cresols; D004791:Enzyme Inhibitors; D007093:Imidazoles; C497761:NOTCH1 protein, human; D011725:Pyridines; D051881:Receptor, Notch1; C032538:4-cresol; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580