Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate.
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.
Jutabha
Promsuk
P
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
Anzai
Naohiko
N
Kitamura
Kenichiro
K
Taniguchi
Atsuo
A
Kaneko
Shuji
S
Yan
Kunimasa
K
Yamada
Hideomi
H
Shimada
Hidetaka
H
Kimura
Toru
T
Katada
Tomohisa
T
Fukutomi
Toshiyuki
T
Tomita
Kimio
K
Urano
Wako
W
Yamanaka
Hisashi
H
Seki
George
G
Fujita
Toshiro
T
Moriyama
Yoshinori
Y
Yamada
Akira
A
Uchida
Shunya
S
Wempe
Michael F
MF
Endou
Hitoshi
H
Sakurai
Hiroyuki
H
D000818:Animals; D002034:Bumetanide / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D004232:Diuretics / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D005665:Furosemide / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism; D006073:Gout / Q000235:genetics / Q000378:metabolism; D006801:Humans; D033461:Hyperuricemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D020125:Mutation, Missense; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D050609:Sodium-Phosphate Cotransporter Proteins, Type I / Q000235:genetics / Q000378:metabolism*; D014503:Urate Oxidase / Q000235:genetics / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism*; D014982:Xenopus laevis
D004232:Diuretics; D051246:Glucose Transport Proteins, Facilitative; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; C493550:SLC17A3 protein, human; C491241:SLC22A12 protein, human; C411811:SLC2A9 protein, human; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; C114338:organic anion transport protein 3; D002034:Bumetanide; D014527:Uric Acid; D005665:Furosemide; D014503:Urate Oxidase
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