A Uremic Solute, P-Cresol, Inhibits the Proliferation of Endothelial Progenitor Cells via the p38 Pathway

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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. Methods and Results: EPCs were isolated from healthy adults and treated with p-cresol (10-80μg/ml) or indoxyl sulfate (25-200μg/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 80μg/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. (Circ J 2011; 75: 2252-2259)