Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity
Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity
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DOI：
10.1097/01.asn.0000022017.96399.b2
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发表时间：
2002-07-01
影响因子：
13.6
通讯作者：
Niwa, T
中科院分区：
文献类型：
--
作者：
Enomoto, A;Takeda, M;Niwa, T
在尿毒症患者中，各种尿毒症毒素积累并对尿毒症发挥各种生物学作用。硫酸吲哚酚（Indoxyl sulfate，IS）是一种来源于膳食蛋白的尿毒症毒素，在尿毒症大鼠和尿毒症患者血清中IS水平均显著升高。以前曾报道IS的蓄积促进慢性肾功能衰竭（CRF）的进展。本研究证实了大鼠有机阴离子转运蛋白（rOATs）在IS转运和诱导其肾毒性中的作用。对5/6肾切除大鼠给予IS导致CRF进展更快，免疫组织化学显示在近端和远端小管中检测到IS，其中rOAT 1（近端小管）和/或rOAT 3（近端和远端小管）也显示出局部化。在体外实验中，建立了稳定表达rOAT 1（S2 rOAT 1）和rOAT 3（S2 rOAT 3）的小鼠近端肾小管上皮细胞。IS抑制S2 rOAT 1和S2 rOAT 3摄取有机阴离子，Ki值分别为34.2和74.4 μ M。与mock相比，S2 rOAT 1和S2 rOAT 3表现出更高水平的IS摄取，这被有机阴离子转运抑制剂丙磺舒和西司他丁抑制。与模拟组相比，添加IS可诱导S2 rOAT 1和S2 rOAT 3的活力降低，丙磺舒可挽救模拟组。这些结果表明，rOAT 1和rOAT 3在IS的跨细胞转运和诱导其肾毒性中起重要作用。
In uremic patients, various uremic toxins are accumulated and exert various biologic effects on uremia. Indoxyl sulfate (IS) is one of uremic toxins that is derived from dietary protein, and serum levels of IS are markedly increased in both uremic rats and patients. It has been previously reported that the accumulation of IS promotes the progression of chronic renal failure (CRF). This study demonstrates the role of rat organic anion transporters (rOATs) in the transport of IS and the induction of its nephrotoxicity. The administration of IS to 5/6-nephrectomized rats caused a faster progression of CRF, and immunohistochemistry revealed that IS was detected in the proximal and distal tubules where rOAT1 (proximal tubules) and/or rOAT3 (proximal and distal tubules) were also shown to be localized. In in vitro study, the proximal tubular cells derived from mouse that stably express rOAT1 (S2 rOAT1) and rOAT3 (S2 rOAT3) were established. IS inhibited organic anion uptake by S2 rOAT1 and S2 rOAT3, and the Ki values were 34.2 and 74.4 muM, respectively. Compared with mock, S2 rOAT1 and S2 rOAT3 exhibited higher levels of IS uptake, which was inhibited by probenecid and cilastatin, organic anion transport inhibitors. The addition of IS induced a decrease in the viability of S2 rOAT1 and S2 rOAT3 as compared with the mock, which was rescued by probenecid. These results suggest that rOAT1 and rOAT3 play an important role in the transcellular transport of IS and the induction of its nephrotoxicity.