Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate

Promsuk Jutabha, Naohiko Anzai, Kenichiro Kitamura, Atsuo Taniguchi, Shuji Kaneko, Kunimasa Yan, Hideomi Yamada, Hidetaka Shimada, Toru Kimura, Tomohisa Katada, Toshiyuki Fukutomi, Kimio Tomita, Wako Urano, Hisashi Yamanaka, George Seki, Toshiro Fujita, Yoshinori Moriyama, Akira Yamada, Shunya Uchida, Michael F. WempeHitoshi Endou, Hiroyuki Sakuraia

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)35123-35132
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number45
DOIs
Publication statusPublished - Nov 5 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Jutabha, P., Anzai, N., Kitamura, K., Taniguchi, A., Kaneko, S., Yan, K., Yamada, H., Shimada, H., Kimura, T., Katada, T., Fukutomi, T., Tomita, K., Urano, W., Yamanaka, H., Seki, G., Fujita, T., Moriyama, Y., Yamada, A., Uchida, S., ... Sakuraia, H. (2010). Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. Journal of Biological Chemistry, 285(45), 35123-35132. https://doi.org/10.1074/jbc.M110.121301