The renal transport protein OATP4C1 mediates uptake of the uremic toxin asymmetric dimethylarginine (ADMA) and efflux of cardioprotective L-homoarginine
The renal transport protein OATP4C1 mediates uptake of the uremic toxin asymmetric dimethylarginine (ADMA) and efflux of cardioprotective L-homoarginine
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DOI：
10.1371/journal.pone.0213747
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发表时间：
2019-03-13
期刊：
影响因子：
3.7
通讯作者：
Koenig, Joerg
中科院分区：
文献类型：
--
作者：
Taghikhani, Emir;Maas, Renke;Koenig, Joerg
尿毒症毒素不对称二甲基精氨酸（ADMA）的血浆浓度升高和L-高精氨酸的血浆浓度降低与心血管事件和总死亡率独立相关。降解ADMA [二甲基氨基水解酶1（DDAH 1）]和合成L-高精氨酸[L-精氨酸：甘氨酸脒基转移酶（AGAT）]的酶在人近曲小管细胞中表达。到目前为止，还不知道近曲小管细胞基底外侧膜中的哪种转运蛋白介导ADMA摄取到细胞中，用于随后的降解或细胞内合成的L-高精氨酸的输出。一项研究表明，摄取转运蛋白OATP 4C 1（基因符号SLCO 4C 1）可能参与ADMA和其他尿毒症毒素的转运。OATP 4C 1是溶质载体SLCO/SLC 21家族的成员，定位于人近端小管细胞的基底外侧膜。通过使用稳定转染的HEK细胞过表达人OATP 4C 1，我们证明ADMA和L-高精氨酸是OATP 4C 1的底物，K-m值分别为232.1 μ M和49.9 μ M。ADMA和结构相关的尿毒症毒素SDMA（100 μ M）抑制OATP 4C 1介导的L-高精氨酸摄取（P < 0.01），而其他检测的尿毒症毒素（如尿素和对甲苯基硫酸盐）对OATP 4C 1介导的转运无影响。预加载实验（300 μ M，60 min）和随后的外排研究显示，OATP 4C 1也促进外排，例如L-高精氨酸。ADMA和L-高精氨酸都是人OATP 4C 1的底物。由于近端小管细胞是ADMA代谢和L-高精氨酸合成的一个位点，因此我们假设OATP 4C 1通过介导体循环中ADMA的摄取和L-高精氨酸的输出而发挥保护作用。
Elevated plasma concentrations of the uremic toxin asymmetrical dimethylarginine (ADMA) and low plasma concentrations of L-homoarginine are independently associated with cardiovascular events and total mortality. Enzymes degrading ADMA [dimethylaminohydrolase 1 (DDAH1)] and synthesizing L-homoarginine [L-arginine:glycine amidinotransferase (AGAT)] are expressed in human proximal tubule cells. So far, it is not known which transport protein in the basolateral membrane of proximal tubule cells is mediating the uptake of ADMA into the cells for subsequent degradation or the export of intracellularly synthesized L-homoarginine. One study suggested that the uptake transporter OATP4C1 (gene symbol SLCO4C1) may be involved in the transport of ADMA and other uremic toxins. OATP4C1 is a member of the SLCO/SLC21 family of solute carriers, localized in the basolateral membrane of human proximal tubule cells. By using stably-transfected HEK cells overexpressing human OATP4C1, we demonstrate that ADMA and L-homoarginine are substrates of OATP4C1 with K-m values of 232.1 mu M and 49.9 mu M, respectively. ADMA and the structurally related uremic toxin SDMA (100 mu M) inhibited OATP4C1-mediated L-homoarginine uptake (P < 0.01), whereas other tested uremic toxins such as urea and p-cresyl sulfate have no effect on OATP4C1-mediated transport. Preloading experiments (300 mu M for 60 min) with subsequent efflux studies revealed that OATP4C1 also facilitates efflux e.g. of L-homoarginine. Both ADMA and L-homoarginine are substrates of human OATP4C1. Because proximal tubule cells are one site of ADMA metabolism and L-homoarginine synthesis, we postulate a protective role of OATP4C1 by mediating uptake of ADMA from and export of L-homoarginine into the systemic circulation.