Indoxyl Sulfate Counteracts Endothelial Effects of Erythropoietin Through Suppression of Akt Phosphorylation

DOI Web Site PubMed 被引用文献5件 参考文献52件
  • Adelibieke Yelixiati
    Department of Advanced Medicine for Uremia, Nagoya University School of Medicine
  • Shimizu Hidehisa
    Department of Advanced Medicine for Uremia, Nagoya University School of Medicine
  • Saito Shinichi
    Department of Advanced Medicine for Uremia, Nagoya University School of Medicine
  • Mironova Roumyana
    Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Science
  • Niwa Toshimitsu
    Department of Advanced Medicine for Uremia, Nagoya University School of Medicine

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Background: Erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). A wide variation in individual response to EPO, however, is often observed, causing EPO resistance. EPO exhibits not only hematopoietic but also extra-hematopoietic functions such as endothelial effects. Indoxyl sulfate, a uremic toxin, is involved in endothelial dysfunction, and consequently, the pathogenesis of CKD-associated cardiovascular disease. The aim of the present study was to determine the effect of indoxyl sulfate on the extra-hematopoietic functions of EPO in human umbilical vein endothelial cells (HUVECs). Methods and Results: HUVECs were incubated with or without indoxyl sulfate or an Akt inhibitor, and then stimulated with or without EPO. Indoxyl sulfate suppressed EPO-induced survival/proliferation, anti-apoptosis function, phosphorylation of endothelial nitric oxide synthase, and the expression of thrombospondin-1, an erythroid-stimulating factor, in HUVECs. Although EPO induced phosphorylation of both Akt and extracellular signal-regulated kinases (ERK) in HUVECs, indoxyl sulfate suppressed phosphorylation of Akt but not ERK. An Akt kinase inhibitor or Akt small interfering RNA suppressed all the EPO-induced cellular effects in HUVECs. As a site of action of indoxyl sulfate on EPO signaling, indoxyl sulfate attenuated EPO-induced tyrosine phosphorylation of EPO receptor (EPOR) in HUVECs. Conclusions: Indoxyl sulfate negatively regulates the EPOR-Akt pathway in endothelial cells, and might contribute to EPO resistance and endothelial dysfunction in patients with CKD.  (Circ J 2013; 77: 1326–1336)<br>

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  • Circulation Journal

    Circulation Journal 77 (5), 1326-1336, 2013

    一般社団法人 日本循環器学会

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