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. Wempe & 2 others Hitoshi Endou, Hiroyuki Sakuraia

Research output: Contribution to journalArticle

83 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

Fingerprint

Sodium-Phosphate Cotransporter Proteins
Secretory Pathway
Uric Acid
Kidney
Pharmaceutical Preparations
Urate Oxidase
Hyperuricemia
Serum
Sodium Potassium Chloride Symporter Inhibitors
Multidrug Resistance-Associated Proteins
Bumetanide
Orphaned Children
Gout
Liver
Furosemide
Missense Mutation
Xenopus
Diuretics
Primates
Oocytes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Jutabha, P., Anzai, N., Kitamura, K., Taniguchi, A., Kaneko, S., Yan, K., ... 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

Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. / Jutabha, Promsuk; Anzai, Naohiko; Kitamura, Kenichiro; Taniguchi, Atsuo; Kaneko, Shuji; Yan, Kunimasa; Yamada, Hideomi; Shimada, Hidetaka; Kimura, Toru; Katada, Tomohisa; Fukutomi, Toshiyuki; Tomita, Kimio; Urano, Wako; Yamanaka, Hisashi; Seki, George; Fujita, Toshiro; Moriyama, Yoshinori; Yamada, Akira; Uchida, Shunya; Wempe, Michael F.; Endou, Hitoshi; Sakuraia, Hiroyuki.

In: Journal of Biological Chemistry, Vol. 285, No. 45, 05.11.2010, p. 35123-35132.

Research output: Contribution to journalArticle

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, Wempe, MF, Endou, H & Sakuraia, H 2010, 'Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate', Journal of Biological Chemistry, vol. 285, no. 45, pp. 35123-35132. https://doi.org/10.1074/jbc.M110.121301
Jutabha, Promsuk ; Anzai, Naohiko ; Kitamura, Kenichiro ; Taniguchi, Atsuo ; Kaneko, Shuji ; Yan, Kunimasa ; Yamada, Hideomi ; Shimada, Hidetaka ; Kimura, Toru ; Katada, Tomohisa ; Fukutomi, Toshiyuki ; Tomita, Kimio ; Urano, Wako ; Yamanaka, Hisashi ; Seki, George ; Fujita, Toshiro ; Moriyama, Yoshinori ; Yamada, Akira ; Uchida, Shunya ; Wempe, Michael F. ; Endou, Hitoshi ; Sakuraia, Hiroyuki. / Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 45. pp. 35123-35132.
@article{16bb7ddd1fcf4b8799aaa38e4d9b29d8,
title = "Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate",
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.",
author = "Promsuk Jutabha and Naohiko Anzai and Kenichiro Kitamura and Atsuo Taniguchi and Shuji Kaneko and Kunimasa Yan and Hideomi Yamada and Hidetaka Shimada and Toru Kimura and Tomohisa Katada and Toshiyuki Fukutomi and Kimio Tomita and Wako Urano and Hisashi Yamanaka and George Seki and Toshiro Fujita and Yoshinori Moriyama and Akira Yamada and Shunya Uchida and Wempe, {Michael F.} and Hitoshi Endou and Hiroyuki Sakuraia",
year = "2010",
month = "11",
day = "5",
doi = "10.1074/jbc.M110.121301",
language = "English",
volume = "285",
pages = "35123--35132",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "45",

}

TY - JOUR

T1 - Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate

AU - Jutabha, Promsuk

AU - Anzai, Naohiko

AU - Kitamura, Kenichiro

AU - Taniguchi, Atsuo

AU - Kaneko, Shuji

AU - Yan, Kunimasa

AU - Yamada, Hideomi

AU - Shimada, Hidetaka

AU - Kimura, Toru

AU - Katada, Tomohisa

AU - Fukutomi, Toshiyuki

AU - Tomita, Kimio

AU - Urano, Wako

AU - Yamanaka, Hisashi

AU - Seki, George

AU - Fujita, Toshiro

AU - Moriyama, Yoshinori

AU - Yamada, Akira

AU - Uchida, Shunya

AU - Wempe, Michael F.

AU - Endou, Hitoshi

AU - Sakuraia, Hiroyuki

PY - 2010/11/5

Y1 - 2010/11/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78049387680&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78049387680&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.121301

DO - 10.1074/jbc.M110.121301

M3 - Article

VL - 285

SP - 35123

EP - 35132

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 45

ER -