Contraluminal para-aminohippurate (PAH) transport in the proximal tubule of the rat kidney
Contraluminal para-aminohippurate (PAH) transport in the proximal tubule of the rat kidney
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大鼠肾近曲小管的腔内对氨基马尿酸 (PAH) 转运
DOI：
10.1007/bf00581838
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
S. Klöss
中科院分区：
文献类型：
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作者：
K. Ullrich;G. Rumrich;G. Fritzsch;S. Klöss
摘要：为了研究对氨基马尿酸（PAH）腔内转运的特异性，测定了脂肪族二羧酸盐对 3H-PAH 内流的抑制效力，以及对 35SO42−- 和 3H-琥珀酸内流的抑制作用，从间质原位进入皮质小管细胞。发现以下结果：1.测试一系列同源二羧酸盐 - 从 2 C 草酸盐到 10 C 癸二酸盐 - PAH 转运均被琥珀酸盐 (app.Ki 1.35 mmol/l) 和所有较长的二羧酸盐抑制，且具有高效能 (app.Ki 0.05–0.35 mmol/l)。硫酸盐转运仅被草酸盐抑制(app.Ki 1.1 mmol/l)，而二羧酸转运被琥珀酸盐、戊二酸盐、己二酸盐和庚二酸盐抑制，且抑制效力递减(app.Ki分别为0.04、0.24、0.91、4.0 mmol/l)。2.PAH转运被琥珀酸盐和戊二酸盐高效抑制。 （app.Ki 1.35 和 0.05 mmol/l），在较小程度上（app.Ki 1.7 和 0.74 mmol/l）由相应的单甲酯产生，但不由二甲酯产生。另一方面，琥珀酸的半醛的Ki值为1.2 mmol/l，与琥珀酸本身具有相同的抑制效力，而戊二酸的二醛（app.Ki 1.4 mmol/l）则比戊二酸的效力低得多。 3.在琥珀酸的2位或氧代基团上引入氧代、甲基或硫羟基基团戊二酸的 2 位上的修饰可适度增强对 PAH 摄取的抑制效力。然而，在 1 位琥珀酸或戊二酸上引入 2-羟基比 d 位更能降低抑制效力。在琥珀酸的 2-3-位引入两个甲基、巯基或羟基会降低或消除其抑制效力。在琥珀酸或戊二酸上引入 2-氨基消除了其对 PAH 转运的影响。然而，N-乙酰化或N-苯甲酰化导致抑制效力恢复。4.反式异构体富马酸盐和中康酸盐抑制PAH-和甲基琥珀酸盐的转运，而顺式异构体马来酸盐和柠康酸盐抑制程度较小或根本不抑制。三羧酸乌头酸酯的效果相反，因为顺式乌头酸酯在反式位置带有CH2延伸的COOH基团，而反式乌头酸酯在顺式位置带有CH2延伸的COOH基团。
数据表明，近端肾小管的管腔细胞侧存在三种不同的阴离子转运系统：1.硫酸盐-草酸盐转运蛋白，2.钠依赖性二羧酸转运蛋白，3.对氨基马尿酸转运蛋白。 PAH 传输系统接受链长高于 7.5 Å（= 末端氧原子之间的距离）的二羧酸盐，而二羧酸盐传输与链长在 6.5 至 10 Å 之间的二羧酸盐相互作用。两种传输系统都更喜欢变换配置。侧基对二羧酸酯与 PAH 传输系统相互作用的影响主要是由于疏水性和电子构型。
AbstractIn order to study the specificity for contraluminal para-aminohippurate (PAH) transport, the inhibitory potency of aliphatic dicarboxylates on3H-PAH influx, as well as the inhibitory effect on35SO42−- and3H-succinate influx, from the interstitium into cortical tubular cells in situ has been determined. The following was found:1.Testing a homologous series of dicarboxylates-ranging from the 2 C oxalate to the 10 C sebacate — PAH transport was inhibited by succinate (app.Ki 1.35 mmol/l), and all longer dicarboxylates, with high potency (app.Ki 0.05–0.35 mmol/l). Sulfate transport was inhibited only by oxalate (app.Ki 1.1 mmol/l), while dicarboxylate transport was inhibited by succinate, glutarate, adipate and pimelate with decreasing potency (app.Ki 0.04, 0.24, 0.91, 4.0 mmol/l, respectively).2.PAH transport was inhibited by succinate and glutarate with high potency (app.Ki 1.35 and 0.05 mmol/l), by the correspondent monomethylester to a lesser extent (app.Ki 1.7 and 0.74 mmol/l), but not by the dimethylester. On the other hand, the semialdehyde of succinate with aKi-value of 1.2 mmol/l, had the same inhibitory potency as succinate itself, while the dialdehyde of glutarate (app.Ki 1.4 mmol/l) was much less potent as glutarate.3.Introduction of an oxo-, methyl- or sulfhydroxylgroup onto the 2-position of succinate, or of an oxo-group onto the 2-position of glutarate moderately augmented the inhibitory potency against PAH-uptake. However, introduction of a 2-hydroxy group onto succinate or glutarate in thel-position reduced the inhibitory potency more than in thed-position. Introduction of two methyl-, sulfhydryl- or hydroxyl-groups in the 2–3-position of succinate reduced or abolished its inhibitory potency. The introduction of a 2-amino group onto succinate or glutarate abolished its effect on PAH transport. However, N-acetylation or N-benzoylation led to a restitution in inhibitory potency.4.The trans-isomers fumarate and mesaconate inhibited PAH- and methylsuccinate transport, while the cis-isomers maleate and citraconate did so to a lesser extent or not at all. The effect was reversed with the tricarboxylic aconitates, because cis-aconitate bears a CH2-extended COOH-group in trans-position and trans-aconitate in cis-position.
The data indicate that there exist three different anion transport systems at the contraluminal cell side of the proximal renal tubule: 1. a sulfate-oxalate transporter, 2. a sodium-dependent dicarboxylate transporter, and 3. a paraaminohippurate transporter. The PAH transport system accepts dicarboxylates with chain length higher than 7.5 Å (=distance between the terminal oxygen atoms), while the dicarboxylate transport interacts with dicarboxylates with a chain length between 6.5 and 10 Å. Both transport systems prefer the transconfiguration. The effect of side groups on the interaction of dicarboxylates with the PAH-transport system is due mainly to hydrophobicity and electron configuration.