Apical voltage-driven urate efflux transporter NPT4 in renal proximal tubule

Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1302-11. doi: 10.1080/15257770.2011.616564.


Uric acid (urate) is the end product of purine metabolism in humans. Human kidneys reabsorb a large proportion of filtered urate. This extensive renal reabsorption, together with the fact that humans do not possess uricase that catalyzes the biotransformation of urate into allantoin, results in a higher plasma urate concentration in humans compared to other mammals. A major determinant of plasma urate concentration is renal excretion as a function of the balance between reabsorption and secretion. We previously identified that renal urate absorption in proximal tubular epithelial cells occurs mainly via apical urate/anion exchanger, URAT1/SLC22A12, and by facilitated diffusion along the trans-membrane potential gradient by the basolateral voltage-driven urate efflux transporter, URATv1/SLC2A9/GLUT9. In contrast, the molecular mechanism by which renal urate secretion occurs remains elusive. Recently, we reported a newly characterized human voltage-driven drug efflux transporter, hNPT4/SLC17A3, which functions as a urate exit pathway located at the apical side of renal proximal tubules. This transporter protein has been hypothesized to play an important role with regard to net urate efflux. An in vivo role of hNPT4 is supported by the fact that missense mutations in SLC17A3 present in hyperuricemia patients with urate underexcretion abolished urate efflux capacity in vitro. Herein, we report data demonstrating that loop diuretics and thiazide diuretics substantially interact with hNPT4. These data provide molecular evidence for loop and thiazide-diuretics-induced hyperuricemia. Thus, we propose that hNPT4 is an important transepithelial proximal tubular transporter that transports diuretic drugs and operates functionally with basolateral organic anion transporters 1/3 (OAT1/OAT3).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Polarity*
  • Electricity*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Humans
  • Kidney Tubules, Proximal / cytology*
  • Kidney Tubules, Proximal / metabolism*
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism*
  • Sodium Potassium Chloride Symporter Inhibitors / chemistry


  • Organic Anion Transporters
  • Sodium Potassium Chloride Symporter Inhibitors
  • urate transporter