Human organic anion transporters function as a high-capacity transporter for p-cresyl sulfate, a uremic toxin
Human organic anion transporters function as a high-capacity transporter for p-cresyl sulfate, a uremic toxin
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DOI：
10.1007/s10157-013-0902-9
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发表时间：
2014-10
影响因子：
2.3
通讯作者：
Hiroshi Watanabe;Yoshiaki Sakaguchi;Ryusei Sugimoto;K. Kaneko;H. Iwata;S. Kotani;M. Nakajima;Yu I
中科院分区：
文献类型：
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作者：
Hiroshi Watanabe;Yoshiaki Sakaguchi;Ryusei Sugimoto;K. Kaneko;H. Iwata;S. Kotani;M. Nakajima;Yu I
背景近年来的临床研究表明，血清中对甲苯基硫酸盐（PCS）（一种尿毒症毒素）水平的升高与慢性肾脏病（CKD）的进展和心血管结局有关。利用大鼠肾皮质切片，我们先前报道了大鼠有机阴离子转运体（OAT）在肾小管分泌PCS中起关键作用。方法利用稳定表达hOAT 1和hOAT 3的HEK 293细胞进行PCS摄取实验。结果PCS可被hOAT 1/HEK 293和hOAT 3/HEK 293细胞摄取，并呈时间和浓度依赖性。hOAT 1介导的PCS转运的表观Km为128 μM，而在hOAT 3/HEK 293中，在5 mM的最高检测PCS浓度下未观察到饱和。丙磺舒是一种OAT抑制剂，可抑制hOAT 1和hOAT 3转运PCS。随着PCS浓度的增加，hOAT 1对对氨基马尿酸的摄取和hOAT 3对雌酮-3-硫酸酯的摄取减少。hOAT 1和hOAT 3对PCS的表观50%抑制浓度分别为690 μM和485 μM。结论PCS是hOAT 1和hOAT 3的底物，hOAT 1和hOAT 3作为一种高容量的PCS转运体发挥生理作用。由于hOAT不仅在肾脏中表达，而且在血管和成骨细胞等中表达，这些发现对于阐明PCS的肾清除、组织分布及其在CKD中的毒性机制具有重要意义。
BackgroundRecent clinical studies have shown that increased serum levels ofp-cresyl sulfate (PCS), a uremic toxin, are associated with the progression of chronic kidney disease (CKD) and cardiovascular outcomes. Using rat renal cortical slices, we previously reported that the rat organic anion transporter (OAT) could play a key role in the renal tubular secretion of PCS. However, no information is currently available regarding the transport of PCS via human OAT (hOAT) isoforms, hOAT1 and hOAT3.MethodsUptake experiments of PCS were performed using HEK293 cells, which stably express hOAT1 or hOAT3.ResultsPCS was taken up by hOAT1/HEK293 and hOAT3/HEK293 cells in a time- and concentration-dependent manner. The apparentKmfor the hOAT1-mediated transport of PCS was 128 μM, whereas in hOAT3/HEK293, saturation was not observed at the highest tested PCS concentration of 5 mM. Probenecid, an OAT inhibitor, inhibited PCS transport by hOAT1 and hOAT3. The uptake ofp-aminohippurate by hOAT1 and estron-3-sulfate by hOAT3 was decreased with increasing PCS concentration. The apparent 50 % inhibitory concentrations for PCS were 690 and 485 μM for hOAT1 and hOAT3, respectively.ConclusionPCS is a substrate for hOAT1 and hOAT3, and hOAT1 and hOAT3 appear to play a physiological role as a high-capacity PCS transporter. Since hOATs are expressed not only in the kidneys, but also in blood vessels and osteoblasts, etc., these findings are of great significance in terms of elucidating the renal clearance, tissue disposition of PCS and the mechanism of its toxicity in CKD.