APICAL VOLTAGE-DRIVEN URATE EFFLUX TRANSPORTER NPT4 IN RENAL PROXIMAL TUBULE
APICAL VOLTAGE-DRIVEN URATE EFFLUX TRANSPORTER NPT4 IN RENAL PROXIMAL TUBULE
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DOI：
10.1080/15257770.2011.616564
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发表时间：
2011-01-01
影响因子：
1.3
通讯作者：
Sakurai, H.
中科院分区：
文献类型：
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作者：
Jutabha, P.;Anzai, N.;Sakurai, H.
尿酸是人体嘌呤代谢的最终产物。人体肾脏会重吸收大部分过滤后的尿酸盐。这种广泛的肾重吸收，加上人类不具有催化尿酸盐生物转化为尿囊素的尿酸酶的事实，导致人类血浆尿酸盐浓度高于其他哺乳动物。血浆尿酸盐浓度的一个主要决定因素是肾排泄，肾排泄是重吸收和分泌之间平衡的函数。我们之前发现，近端肾小管上皮细胞中的肾脏尿酸盐吸收主要通过顶端尿酸盐/阴离子交换剂URAT 1/SLC 22 A12以及基底侧电压驱动的尿酸盐外排转运蛋白URATv 1/SLC 2A 9/GLUT 9沿跨膜电位梯度的易化扩散沿着进行。相比之下，肾脏尿酸盐分泌的分子机制仍然难以捉摸。最近，我们报道了一个新的特点，人类电压驱动的药物外排转运蛋白，hNPT 4/SLC 17 A3，其功能作为尿酸盐出口途径位于肾近端小管的顶侧。这种转运蛋白已被假设为在净尿酸盐流出方面发挥重要作用。hNPT 4在体内的作用得到了以下事实的支持，即存在于尿酸盐排泄不足的高尿酸血症患者中的SLC 17 A3中的错义突变在体外消除了尿酸盐外排能力。在此，我们报告的数据表明，袢利尿剂和噻嗪类利尿剂基本上与hNPT 4相互作用。这些数据为袢和噻嗪类利尿剂诱导的高尿酸血症提供了分子证据。因此，我们建议，hNPT 4是一个重要的跨上皮近端肾小管转运蛋白，转运利尿药物，并与基底外侧有机阴离子转运蛋白1/3（OAT 1/OAT 3）的功能。
Uric acid (urate) is the end product of purine metabolism in humans. Human kidneys reabsorb a large proportion of filtered urate. This extensive renal reabsorption, together with the fact that humans do not possess uricase that catalyzes the biotransformation of urate into allantoin, results in a higher plasma urate concentration in humans compared to other mammals. A major determinant of plasma urate concentration is renal excretion as a function of the balance between reabsorption and secretion. We previously identified that renal urate absorption in proximal tubular epithelial cells occurs mainly via apical urate/anion exchanger, URAT1/SLC22A12, and by facilitated diffusion along the trans-membrane potential gradient by the basolateral voltage-driven urate efflux transporter, URATv1/SLC2A9/GLUT9. In contrast, the molecular mechanism by which renal urate secretion occurs remains elusive. Recently, we reported a newly characterized human voltage-driven drug efflux transporter, hNPT4/SLC17A3, which functions as a urate exit pathway located at the apical side of renal proximal tubules. This transporter protein has been hypothesized to play an important role with regard to net urate efflux. An in vivo role of hNPT4 is supported by the fact that missense mutations in SLC17A3 present in hyperuricemia patients with urate under-excretion abolished urate efflux capacity in vitro. Herein, we report data demonstrating that loop diuretics and thiazide diuretics substantially interact with hNPT4. These data provide molecular evidence for loop and thiazide-diuretics-induced hyperuricemia. Thus, we propose that hNPT4 is an important transepithelial proximal tubular transporter that transports diuretic drugs and operates functionally with basolateral organic anion transporters 1/3 (OAT1/OAT3).