Organic anion transporter 1 (OAT1) involved in renal cell transport of aristolochic acid I
Organic anion transporter 1 (OAT1) involved in renal cell transport of aristolochic acid I
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DOI：
10.1177/0960327111424302
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发表时间：
2012-08
影响因子：
2.8
通讯作者：
Youjia Zeng;Rong-Yi Zhang;Jin-Lang Wu;Mengzhong Liu;Wenxing Peng;Xinghuo Yu;Xiao Yang
中科院分区：
文献类型：
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作者：
Youjia Zeng;Rong-Yi Zhang;Jin-Lang Wu;Mengzhong Liu;Wenxing Peng;Xinghuo Yu;Xiao Yang
马兜铃酸（Aristolochic Acids，AA）是一个结构上相关的硝基菲羧酸家族，存在于药用植物如马兜铃属物种中。位于肾近端小管的溶质载体（SLC 22）基因家族的有机阴离子转运蛋白（OAT）在多种外源性和内源性化合物的排泄中起关键作用。然而，目前还不清楚AA如何渗透到肾上皮细胞。在这方面，我们研究了大鼠OAT 1（[rOAT 1] SLC 22 A6）在体外和体内AAI细胞摄取中的作用。在rOAT 1转染的人胚肾293（HEK 293）细胞中观察到AAI的浓度和时间依赖性细胞内蓄积，其比对照细胞高2- 6倍。AAI处理后，rOAT 1转染的HEK 293细胞的细胞凋亡率显著高于对照细胞。对氨基马尿酸（PAH）显著降低了rOAT 1转染的HEK 293细胞中AAI的细胞内蓄积。AAI给药35天后，大鼠基底外侧膜OAT 1表达显著降低，PAH的肾脏清除率下降，肾近端小管损伤。这些发现表明，AAI被OAT 1吸收，然后对肾近端小管细胞产生细胞内毒性作用，进而损害功能性OAT 1，并可能进一步干扰其底物的转运。
Aristolochic acids (AAs) are a family of structurally related nitrophenanthrene carboxylic acids that are present in medicinal herbs such as Aristolochia species. The organic anion transporters (OATs) of the solute carrier (SLC22) gene family located in the renal proximal tubules play a key role in the excretion of a variety of exogenous and endogenous compounds. However, it is unclear how AAs permeate into renal epithelial cells. In this regard, we investigated the role of rat OAT1 ([rOAT1] SLC22A6) in the cellular uptake of AAI in vitro and in vivo. A concentration- and time-dependent intracellular accumulation of AAI was observed in rOAT1-transfected human embryonic kidney 293 (HEK293) cells, which was 2- to 6-fold higher than the control cells. There was a significantly increased rate of cellular apoptosis in rOAT1-transfected HEK293 cells than control cells after AAI treatment. Para-aminohippuric acid (PAH) significantly reduced the intracellular accumulation of AAI in rOAT1-transfected HEK293 cells. Administration of AAI for 35 days in rats caused significantly reduced expression of OAT1 in basolateral membrane and declined renal clearance of PAH as well as renal proximal tubule injuries. These findings indicate that AAI is taken up by OAT1, which then exert its intracellular toxic effects on renal proximal tubule cells, which in turn damage functional OAT1 and may further disturb the transport of its substrates.