Elevated plasma concentrations of the uremic toxin asymmetric dimethylarginine (ADMA) and low plasma concentrations of l-homoarginine are independently associated with cardiovascular events and mortality. Key enzymes involved in the homeostasis of both arginine derivatives are expressed in proximal tubule cells of the kidney. To get access to these enzymes, transport proteins are important. One of the transporters mediating the transport of ADMA and l-homoarginine is the solute carrier superfamily (SLC) member OATP4C1, located in the basolateral membrane of proximal tubule cells. To gain insights into the role of export pumps in the transport of both substances, we established a double-transfected MDCK cell line expressing OATP4C1 and the export pump P-glycoprotein (P-gp). Using MDCK cell monolayers, we demonstrated in time-dependent and concentration-dependent vectorial transport experiments that ADMA and l-homoarginine are transported from the basolateral to the apical compartment of MDCK-OATP4C1-P-gp cells with significantly higher transport rates compared to single-transfected MDCK-OATP4C1, MDCK-P-gp and MDCK-VC (control) cells (e.g. transport ratio MDCK-OATP4C1-P-gp/MDCK-VC: for 50 µM ADMA = 2.0-fold, for 50 µM l-homoarginine = 3.4-fold). These results indicate that both OATP4C1 and P-gp transport the arginine derivatives ADMA and l-homoarginine and are, therefore, important for the homoeostasis of both substances.

中文翻译：

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在双转染的MDCK细胞中研究了OATP4C1和P-糖蛋白对精氨酸衍生物不对称二甲基精氨酸（ADMA）和L-高精氨酸的向量转运。

尿毒症毒素不对称二甲基精氨酸（ADMA）的血浆浓度升高和1- homo精氨酸的血浆浓度低与心血管事件和死亡率独立相关。两种精氨酸衍生物的体内稳态均涉及的关键酶在肾脏的近端小管细胞中表达。为了获得这些酶，转运蛋白很重要。转运ADMA和l的运输者之一-高精氨酸是溶质载体超家族（SLC）成员OATP4C1，位于近端小管细胞的基底外侧膜中。为了深入了解出口泵在两种物质的运输中的作用，我们建立了表达OATP4C1和出口泵P-糖蛋白（P-gp）的双转染MDCK细胞系。使用MDCK细胞单层，我们在时间依赖性和浓度依赖性矢量转运实验中证明了ADMA和1- homo精氨酸从MDCK-OATP4C1-P-gp细胞的基底外侧转运至顶端区室，与单个细胞相比，转运速率明显更高-转染的MDCK-OATP4C1，MDCK-P-gp和MDCK-VC（对照）细胞（例如，运输比MDCK-OATP4C1-P-gp / MDCK-VC：对于50 µM ADMA = 2.0倍，对于50 µM l-高精氨酸= 3.4倍）。这些结果表明，OATP4C1和P-gp都运输精氨酸衍生物ADMA和1-高精氨酸，因此，对于这两种物质的均稳态而言都是重要的。