Urinary Dopamine as a Potential Index of the Transport Activity of Multidrug and Toxin Extrusion in the Kidney.
Urinary Dopamine as a Potential Index of the Transport Activity of Multidrug and Toxin Extrusion in the Kidney.
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DOI：
10.3390/ijms17081228
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发表时间：
2016-07-30
影响因子：
5.6
通讯作者：
Masuda S
中科院分区：
文献类型：
--
作者：
Kajiwara M;Ban T;Matsubara K;Nakanishi Y;Masuda S
多巴胺是一种阳离子利钠剂儿茶酚胺，在分泌到管腔之前在肾脏的近端小管细胞(PTCs)合成，管腔是其作用的关键部位。然而，多巴胺分泌到管腔的分子机制仍不清楚。多药毒素排泄(Mate)是一种H+/有机阳离子逆向转运蛋白，在PTCs刷状缘膜上高表达，并介导包括二甲双胍和顺铂在内的有机阳离子从上皮细胞流出到尿液中。因此，我们假设Mate介导了多巴胺的分泌，一种阳离子儿茶酚胺，进入小管腔，从而调节利钠。在这里，我们证明了在人(H)MATE-1-、hMATE-2K-和小鼠(M)Mate表达细胞中摄取[~3H]多巴胺呈现饱和动力学。与野生型小鼠相比，Mate1基因敲除小鼠的体液滞留和尿多巴胺和Na+排泄减少。Mate抑制剂伊马替尼以浓度依赖的方式抑制hMATE_1、hMATE_2-K和mMATE_1表达的细胞摄取[~3H]多巴胺。在临床相关浓度下，伊马替尼抑制表达hMATE1和hMATE2-K的细胞摄取[~3H]多巴胺。伊马替尼治疗的小鼠尿多巴胺和Na+排泄减少，并出现液体滞留。总之，Mate转运体分泌肾合成的多巴胺，因此，尿多巴胺有可能成为Mate转运体活性的一个指标。
Dopamine is a cationic natriuretic catecholamine synthesized in proximal tubular cells (PTCs) of the kidney before secretion into the lumen, a key site of its action. However, the molecular mechanisms underlying dopamine secretion into the lumen remain unclear. Multidrug and toxin extrusion (MATE) is a H+/organic cation antiporter that is highly expressed in the brush border membrane of PTCs and mediates the efflux of organic cations, including metformin and cisplatin, from the epithelial cells into the urine. Therefore, we hypothesized that MATE mediates dopamine secretion, a cationic catecholamine, into the tubule lumen, thereby regulating natriuresis. Here, we show that [3H]dopamine uptake in human (h) MATE1-, hMATE-2K- and mouse (m) MATE-expressing cells exhibited saturable kinetics. Fluid retention and decreased urinary excretion of dopamine and Na+ were observed in Mate1-knockout mice compared to that in wild-type mice. Imatinib, a MATE inhibitor, inhibited [3H]dopamine uptake by hMATE1-, hMATE2-K- and mMATE1-expressing cells in a concentration-dependent manner. At clinically-relevant concentrations, imatinib inhibited [3H]dopamine uptake by hMATE1- and hMATE2-K-expressing cells. The urinary excretion of dopamine and Na+ decreased and fluid retention occurred in imatinib-treated mice. In conclusion, MATE transporters secrete renally-synthesized dopamine, and therefore, urinary dopamine has the potential to be an index of the MATE transporter activity.
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影响因子：
2.1
作者：
Kajiwara, Moto;Masuda, Satohiro;Inui, Ken-ichi
通讯作者：
Inui, Ken-ichi
影响因子：
15.9
作者：
ALEXANDER, RW;GILL, JR;KEISER, HR
通讯作者：
KEISER, HR
影响因子：
4.8
作者：
Chan, BS;Satriano, JA;Schuster, VL
通讯作者：
Schuster, VL
影响因子：
4.1
作者：
INUI, K;SAITO, H;HORI, R
通讯作者：
HORI, R
DOI：
10.1016/j.bbadis.2010.02.004
发表时间：
2010-12
影响因子：
6.2
作者：
Jose, Pedro A.;Soares-da-Silva, Patricio;Eisner, Gilbert M.;Felder, Robin A.
通讯作者：
Felder, Robin A.