An oral adsorbent, AST-120 protects against the progression of oxidative stress by reducing the accumulation of indoxyl sulfate in the systemic circulation in renal failure
An oral adsorbent, AST-120 protects against the progression of oxidative stress by reducing the accumulation of indoxyl sulfate in the systemic circulation in renal failure
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DOI：
10.1007/s11095-007-9248-x
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发表时间：
2007-07-01
影响因子：
3.7
通讯作者：
Otagiri, Masaki
中科院分区：
文献类型：
--
作者：
Shimoishi, Kazuki;Anraku, Makoto;Otagiri, Masaki
目的.研究了AST-120（一种口服吸附剂）对慢性肾功能衰竭（CRF）体循环中氧化应激的影响，并研究了AST-120吸附的尿毒症毒素硫酸吲哚酚（IS）在体外和体内诱导血管系统中活性氧（ROS）形成的潜在作用。氧化白蛋白的水平，体循环中氧化应激的标志物，通过HPLC测定，如前所述。通过定量RT-PCR测定TGF-β 1和Oat 1的mRNA水平。用荧光酶标仪检测IS诱导的人脐静脉内皮细胞（HUVECs）活性氧的产生。与对照组相比，使用5/6肾切除大鼠（CRF大鼠）确定氧化与未氧化白蛋白的比率增加。该比率在接受AST-120 4周的组中显著降低，表明AST-120抑制CRF中的氧化应激。在具有相似肾功能的CRF大鼠中也观察到AST-120的抗氧化作用。氧化白蛋白的比例与体内血清IS水平相关。在CRF大鼠中也观察到相同的关系与持续给药的IS。此外，IS可显著增加HUVEC内ROS的生成，且呈剂量和时间依赖性，提示IS的蓄积可能在增强血管内氧化应激中起重要作用。我们认为AST-120降低了血液中诱导内皮细胞产生ROS的IS浓度，从而抑制了肾衰竭时体循环中随后发生的氧化应激。
Purpose. The effect of AST-120, an oral adsorbent, on oxidative stress in the systemic circulation in chronic renal failure (CRF) was examined and the potential role of indoxyl sulfate (IS), an uremic toxin adsorbed by AST-120, in inducing the formation of reactive oxygen species (ROS) in the vascular system was studied, in vitro and in vivo.Materials and methods. The level of oxidized albumin, a marker for oxidative stress in the systemic circulation was determined by HPLC, as previously reported. The mRNA levels of TGF-beta(1), and Oat1 were measured by quantitative RT-PCR. The IS induced ROS generation in cultured human umbilical vein endothelial cells (HUVECs) was estimated using a fluorescence microplate reader.Results. An increase in the ratio of oxidized to unoxidized albumin was determined using 5/6 nephrectomized rats (CRF rats) compared to a control group. The ratio was significantly reduced in the group that received AST-120 of 4 weeks, suggesting that AST-120 inhibits oxidative stress in CRF. An anti-oxidative effect of AST-120 was also observed in CRF rats with a similar renal function. The ratio of oxidized albumin was correlated with serum IS levels in vivo. The same relationship was also observed in CRF rats with the continued administration of IS. In addition, IS dramatically increased the generation of ROS in both a dose- and time- dependent manner in HUVEC, suggesting that accumulated IS may play an important role in enhancing intravascular oxidative stress.Conclusion. We propose that AST-120 reduces IS concentrations in the blood that induces ROS production in endothelial cells, thereby inhibiting the subsequent occurrence of oxidative stress in the systemic circulation in renal failure.