Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate.
Summary of "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.
Affiliation
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
Journal Details
This article was published in the following journal.
Name: The Journal of biological chemistry
ISSN: 1083-351X
Pages: 35123-32
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20810651
- DOI: http://dx.doi.org/10.1074/jbc.M110.121301
Medical and Biotech [MESH] Definitions
Sodium-phosphate Cotransporter Proteins, Type Iic
A non-electrogenic sodium-dependent phosphate transporter. It is found primarily in apical membranes of PROXIMAL RENAL TUBULES.
Sodium-phosphate Cotransporter Proteins, Type Iia
An electrogenic sodium-dependent phosphate transporter. It is present primarily in BRUSH BORDER membranes of PROXIMAL RENAL TUBULES.
Sodium-phosphate Cotransporter Proteins, Type Iib
A sodium-dependent phosphate transporter present primarily at apical sites of EPITHELIAL CELLS in the SMALL INTESTINE.
Sodium-phosphate Cotransporter Proteins, Type Ii
A family of sodium-phosphate cotransporter proteins with eight transmembrane domains. They are present primarily in the KIDNEY and SMALL INTESTINE and are responsible for renal and small intestinal epithelial transport of phosphate.
Glycosuria, Renal
An autosomal inherited disorder due to defective reabsorption of GLUCOSE by the PROXIMAL RENAL TUBULES. The urinary loss of glucose can reach beyond 50 g/day. It is attributed to the mutations in the SODIUM-GLUCOSE TRANSPORTER 2 encoded by the SLC5A2 gene.
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