title: Functional cooperation of URAT1 (SLC22A12) and URATv1 (SLC2A9) in renal reabsorption of urate.
abstract: BACKGROUND
  Serum urate (SUA) level is affected by alteration in urinary reabsorption caused by clinically important drugs; however, there are no experimental models suitable to assess their effect on renal reabsorption. We, therefore, aimed to establish an experimental system co-expressing the urate transporters URAT1 (SLC22A12) and URATv1 (SLC2A9) (designated UUv cells) at the apical and basolateral membranes, respectively.
  
  
  METHODS
  Apical uptake and vectorial transport of [(14)C]urate in the apical-to-basolateral direction in UUv cells were measured in the presence or absence of uricosuric benzbromarone or anti-uricosuric trans-stimulators.
  
  
  RESULTS
  The urate permeability in the apical-to-basolateral direction remarkably increased by 7.0-fold in UUv cells, compared with non-transfected mock cells. The apical-to-basolateral transport was cis-inhibited by benzbromarone, but trans-stimulated by pyrazinecarboxylic acid and monocarboxylates such as nicotinate and lactate. Furthermore, salicylate showed both trans-stimulation and cis-inhibition in the urate transport at low and high concentrations, respectively. Finally, coexpression of URAT1 and URATv1 in human kidney epithelial cells was exhibited immunohistochemically.
  
  
  CONCLUSIONS
  It is demonstrated that functional cooperation of URAT1 and URATv1 is essential for renal reabsorption of urate, and in the established system influence of drugs on SUA is reflected in the alteration of urate permeability across the renal tubular epithelial cells.
authors.affiliation: Department of Membrane Transport and Biopharmaceutics, Kanazawa University, Kakuma-machi, Kanazawa , Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Kouhei
authors.initials: K
authors.lastname: Ohya
authors.forename: Sho
authors.initials: S
authors.lastname: Shimada
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000818:Animals; D001553:Benzbromarone / Q000494:pharmacology; D002478:Cells, Cultured; D004285:Dogs; D005455:Fluorescent Antibody Technique; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D019344:Lactic Acid / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D009525:Niacin / Q000494:pharmacology; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D011718:Pyrazinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D014527:Uric Acid / Q000097:blood*; D014528:Uricosuric Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014982:Xenopus laevis / Q000378:metabolism*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C411811:SLC2A9 protein, human; D014528:Uricosuric Agents; D014665:Vasodilator Agents; D009525:Niacin; D014527:Uric Acid; D011718:Pyrazinamide; C005296:pyrazinoic acid; D019344:Lactic Acid; D001553:Benzbromarone