Transport of the uremic toxin symmetric dimethylarginine (SDMA) by renal transport proteins.

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lorenz A Scherpinski, Martin F Fromm, Renke Maas, Jörg König
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引用次数: 0

Abstract

The L-arginine derivative and uremic toxin symmetric dimethylarginine (SDMA) is an independent risk marker for total mortality and cardiovascular events. Interferences with L-arginine- or L-homoarginine-related signaling, metabolism, or transport have been proposed as underlying mechanisms. SDMA is endogenously formed and predominantly eliminated via the kidney. Whereas for L-arginine and other L-arginine derivatives such as L-homoarginine and asymmetric dimethylarginine (ADMA) key transport proteins involved in the cellular uptake and release have been characterized, comparable data for the transport of SDMA are lacking.Using HEK cell lines overexpressing the transport proteins OCT2, OATP4C1, MATE1, OAT4, and OAT10, which are all expressed in renal proximal tubule cells, and the ubiquitously-expressed transport protein CAT1 we performed uptake experiments demonstrating that SDMA is a substrate for CAT1, OATP4C1, OCT2, and MATE1 in physiological concentrations, but not of OAT4 and OAT10. Km values for OATP4C1-, CAT1-, and MATE1-mediated SDMA uptake were 70 µM, 246 µM, and 1 973 µM, respectively. For OCT2-mediated uptake, no saturation could be reached, precluding the determination of a Km value. Uptake of SDMA by these transporters could be inhibited by known substrates of the respective transport proteins. Furthermore, CAT1 and OATP4C1 also mediate the efflux of SDMA out of cells.These results show that SDMA is a substrate of renally-expressed transport proteins OATP4C1, OCT2, and MATE1 and of CAT1 demonstrating that these transporters are involved in the homeostasis of this uremic toxin and possible sites of interactions with related compounds.

肾转运蛋白转运尿毒症毒素对称二甲基精氨酸(SDMA)。
l -精氨酸衍生物和尿毒症毒素对称二甲基精氨酸(SDMA)是总死亡率和心血管事件的独立危险标志物。对l -精氨酸或l -同型精氨酸相关信号、代谢或运输的干扰被认为是潜在的机制。SDMA是内源性形成的,主要通过肾脏消除。对于l -精氨酸和其他l -精氨酸衍生物,如l -同型精氨酸和不对称二甲基精氨酸(ADMA),参与细胞摄取和释放的关键转运蛋白已经被表征,但SDMA转运的可比较数据缺乏。利用HEK细胞系过表达转运蛋白OCT2、OATP4C1、MATE1、OAT4和OAT10(这些蛋白均在肾近端小管细胞中表达)和普遍表达的转运蛋白CAT1,我们进行了摄取实验,证明SDMA是生理浓度下CAT1、OATP4C1、OCT2和MATE1的底物,但不是OAT4和OAT10的底物。OATP4C1-、CAT1-和mate1介导的SDMA摄取Km值分别为70µM、246µM和1973µM。对于oct2介导的摄取,无法达到饱和,因此无法确定Km值。这些转运蛋白对SDMA的摄取可以被各自转运蛋白的已知底物所抑制。此外,CAT1和OATP4C1也介导SDMA向细胞外的外排。这些结果表明,SDMA是肾脏表达的转运蛋白OATP4C1、OCT2和MATE1和CAT1的底物,表明这些转运蛋白参与了这种尿毒症毒素的稳态,并可能与相关化合物相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Amino Acids
Amino Acids 生物-生化与分子生物学
CiteScore
6.40
自引率
5.70%
发文量
99
审稿时长
2.2 months
期刊介绍: Amino Acids publishes contributions from all fields of amino acid and protein research: analysis, separation, synthesis, biosynthesis, cross linking amino acids, racemization/enantiomers, modification of amino acids as phosphorylation, methylation, acetylation, glycosylation and nonenzymatic glycosylation, new roles for amino acids in physiology and pathophysiology, biology, amino acid analogues and derivatives, polyamines, radiated amino acids, peptides, stable isotopes and isotopes of amino acids. Applications in medicine, food chemistry, nutrition, gastroenterology, nephrology, neurochemistry, pharmacology, excitatory amino acids are just some of the topics covered. Fields of interest include: Biochemistry, food chemistry, nutrition, neurology, psychiatry, pharmacology, nephrology, gastroenterology, microbiology
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