Human Sodium Phosphate Transporter 4 (hNPT4/SLC17A3) as a Common Renal Secretory Pathway for Drugs and Urate
Human Sodium Phosphate Transporter 4 (hNPT4/SLC17A3) as a Common Renal Secretory Pathway for Drugs and Urate
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DOI：
10.1074/jbc.m110.121301
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发表时间：
2010-11-05
影响因子：
4.8
通讯作者：
Sakurai, Hiroyuki
中科院分区：
文献类型：
--
作者：
Jutabha, Promsuk;Anzai, Naohiko;Sakurai, Hiroyuki
肝脏尿酸氧化酶（尿酸酶）的进化性丧失导致人类血清尿酸（尿酸盐）升高。尿酸酶的丧失可能对早期灵长类动物的生存有益。然而，血清尿酸盐升高使人易患高尿酸血症，高尿酸血症是一种代谢紊乱，导致痛风、高血压和各种心血管疾病。人血清尿酸盐水平主要由肾脏中尿酸盐的重吸收和分泌决定。肾脏尿酸盐重吸收通过两种近端肾小管尿酸盐转运蛋白控制：顶端URAT 1（SLC 22 A12）和基底外侧URATv 1/GLUT 9（SLC 2A 9）。相反，肾脏尿酸盐分泌的分子机制仍然未知。在这份报告中，我们证明了孤儿转运蛋白hNPT 4（人磷酸钠转运蛋白4; SLC 17 A3）是一种多特异性的有机阴离子外排转运蛋白，在肾脏和肝脏中表达。hNPT 4定位于肾小管顶侧，作为电压驱动的尿酸盐转运蛋白发挥作用。此外，袢利尿剂，如呋塞米和布美他尼，基本上与hNPT 4相互作用。因此，这种蛋白可能作为两种药物的共同分泌途径，并可能在利尿剂诱导的高尿酸血症中发挥重要作用。hNPT 4在体内的作用是由两个SLC 17 A3错义突变的高尿酸血症患者提出的。这些突变的hNPT 4版本在爪蟾卵母细胞中表达时表现出降低的尿酸盐流出。我们的研究结果将完成肾小管细胞中尿酸盐分泌的模型，其中通过OAT 1和/或OAT 3从血液中摄取的细胞内尿酸盐通过hNPT 4从细胞中排出进入管腔。
The evolutionary loss of hepatic urate oxidase (uricase) has resulted in humans with elevated serum uric acid (urate). Uricase loss may have been beneficial to early primate survival. However, an elevated serum urate has predisposed man to hyperuricemia, a metabolic disturbance leading to gout, hypertension, and various cardiovascular diseases. Human serum urate levels are largely determined by urate reabsorption and secretion in the kidney. Renal urate reabsorption is controlled via two proximal tubular urate transporters: apical URAT1 (SLC22A12) and basolateral URATv1/GLUT9 (SLC2A9). In contrast, the molecular mechanism(s) for renal urate secretion remain unknown. In this report, we demonstrate that an orphan transporter hNPT4 (human sodium phosphate transporter 4; SLC17A3) was a multispecific organic anion efflux transporter expressed in the kidneys and liver. hNPT4 was localized at the apical side of renal tubules and functioned as a voltage-driven urate transporter. Furthermore, loop diuretics, such as furosemide and bumetanide, substantially interacted with hNPT4. Thus, this protein is likely to act as a common secretion route for both drugs and may play an important role in diuretics-induced hyperuricemia. The in vivo role of hNPT4 was suggested by two hyperuricemia patients with missense mutations in SLC17A3. These mutated versions of hNPT4 exhibited reduced urate efflux when they were expressed in Xenopus oocytes. Our findings will complete a model of urate secretion in the renal tubular cell, where intracellular urate taken up via OAT1 and/or OAT3 from the blood exits from the cell into the lumen via hNPT4.