Critical Role of Organic Anion Transporters 1 and 3 in Kidney Accumulation and Toxicity of Aristolochic Acid I
Critical Role of Organic Anion Transporters 1 and 3 in Kidney Accumulation and Toxicity of Aristolochic Acid I
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DOI：
10.1021/mp100418u
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发表时间：
2011-11-01
影响因子：
4.9
通讯作者：
Ren, Jin
中科院分区：
文献类型：
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作者：
Xue, Xiang;Gong, Li-Kun;Ren, Jin
马兜铃酸（AA），特别是其主要成分马兜铃酸I（AAI）的摄入，导致严重的肾损伤，称为马兜铃酸肾病（AAN）。尽管肝细胞色素P450代谢AAI以降低其在小鼠中的肾毒性，但AAI被肾细胞摄取以诱导肾毒性的机制在很大程度上是未知的。在这项研究中，我们发现，有机阴离子转运蛋白（OATs）1和3，已知的蛋白质运输药物从血液进入肾小管上皮细胞，负责运输AM进入肾小管细胞和随后的肾功能。与对照细胞相比，稳定转染人OAT 1或OAT 3的HEK 293细胞中的AAI摄取大大增加，并且该摄取依赖于AAI浓度。丙磺舒，一种众所周知的OAT抑制剂，给药的小鼠减少AAI肾蓄积和尿排泄，并保护小鼠免受AM诱导的急性肾小管坏死。此外，与野生型小鼠相比，Oat1和OAT3基因敲除小鼠中AAI的肾蓄积和由AAI诱导的严重肾脏病变均被显著抑制。总之，我们的研究结果表明，OAT 1和OAT 3在AAl肾蓄积和毒性中具有关键作用。这些转运蛋白可能作为抗AAN的潜在治疗靶点。
Ingestion of atistolochic acid (AA), especially its major constituent aristolochic acid I (AAI), results in severe kidney injury known as aristolochic acid nephropathy (AAN). Although hepatic cytochrome P450s metabolize AAI to reduce its kidney toxicity in mice, the mechanism by which AAI is uptaken by renal cells to induce renal toxicity is largely unknown. In this study, we found that organic anion transporters (OATs) 1 and 3, proteins known to transport drugs from the blood into the tubular epithelium, are responsible for the transportation of AM into renal tubular cells and the subsequent nephrotoincity. AAI uptake in HEK 293 cells stably transfected with human OAT1 or OAT3 was greatly increased compared to that in the control cells, and this uptake was dependent on the AAI concentration. Administration of probenecid, a well-known OAT inhibitor, to the mice reduced AAI renal accumulation and its urinary excretion and protected mice from AM-induced acute tubular necrosis. Further, AAI renal accumulation and severe kidney lesions induced by AAl in Oat1 and OAT3 gene knockout mice all were markedly suppressed compared to those in the wild-type mice. Together, our results suggest that OAT1 and OAT3 have a critical role in AAlrenal accumulation and toxicity. These transporters may serve as a potential therapeutic target against AAN.