Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
PLoS One. 2019 Mar 13;14(3):e0213747. doi: 10.1371/journal.pone.0213747. eCollection 2019.
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 Km values of 232.1 μM and 49.9 μM, respectively. ADMA and the structurally related uremic toxin SDMA (100 μM) 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 μM 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.
血浆中尿毒症毒素不对称二甲基精氨酸 (ADMA) 的浓度升高和 L-同型精氨酸的浓度降低与心血管事件和总死亡率独立相关。降解 ADMA 的酶 [二甲基精氨酸二甲胺水解酶 1 (DDAH1)] 和合成 L-同型精氨酸 [L-精氨酸：甘氨酸酰胺转移酶 (AGAT)] 在人近端肾小管细胞中表达。到目前为止，尚不清楚近端肾小管细胞基底外侧膜中的哪种转运蛋白介导 ADMA 进入细胞进行随后的降解，或者介导细胞内合成的 L-同型精氨酸的输出。一项研究表明，摄取转运蛋白 OATP4C1（基因符号 SLCO4C1）可能参与 ADMA 和其他尿毒症毒素的转运。OATP4C1 是溶质载体 SLCO/SLC21 家族的成员，定位于人近端肾小管细胞的基底外侧膜。通过使用稳定转染的过表达人 OATP4C1 的 HEK 细胞，我们证明 ADMA 和 L-同型精氨酸是 OATP4C1 的底物，Km 值分别为 232.1 μM 和 49.9 μM。ADMA 和结构上相关的尿毒症毒素 SDMA（100 μM）抑制 OATP4C1 介导的 L-同型精氨酸摄取（P < 0.01），而其他测试的尿毒症毒素，如尿素和对甲酚硫酸盐，对 OATP4C1 介导的转运没有影响。预加载实验（300 μM 持续 60 min）和随后的外排研究表明，OATP4C1 还促进 L-同型精氨酸的外排，例如。ADMA 和 L-同型精氨酸都是人 OATP4C1 的底物。由于近端肾小管细胞是 ADMA 代谢和 L-同型精氨酸合成的一个部位，我们推测 OATP4C1 通过介导 ADMA 的摄取和 L-同型精氨酸进入全身循环的输出，发挥保护作用。
