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

被引:40
作者
Adelibieke, Yelixiati [1 ]
Shimizu, Hidehisa [1 ]
Saito, Shinichi [1 ]
Mironova, Roumyana [2 ]
Niwa, Toshimitsu [1 ]
机构
[1] Nagoya Univ, Grad Sch Med, Dept Adv Med Uremia, Nagoya, Aichi 4668550, Japan
[2] Bulgarian Acad Sci, Inst Mol Biol Roumen Tsanev, Sofia, Bulgaria
关键词
Cardiovascular disease; Chronic kidney disease; Endothelial cells; Erythropoietin resistance; Indoxyl sulfate; NF-KAPPA-B; NITRIC-OXIDE SYNTHASE; SITE-SELECTIVE DEPHOSPHORYLATION; FACTOR-BETA-RECEPTOR; GROWTH-FACTOR-I; UREMIC TOXIN; OXIDATIVE STRESS; CELLS; EXPRESSION; PROLIFERATION;
D O I
10.1253/circj.CJ-12-0884
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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)
引用
收藏
页码:1326 / 1336
页数:11
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