Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney

Tsuneo Deguchi, Sumio Ohtsuki, Masaki Otagiri, Hitomi Takanaga, Hiroshi Asaba, Shinobu Mori, Tetsuya Terasaki

Research output: Contribution to journalArticlepeer-review

104 Citations (Scopus)

Abstract

Background. Indoxyl sulfate is a uremic toxin that accumulates in the body because of the patient's inability to excrete it and it induces a number of uremic symptoms and leads to chronic renal failure. The functional failure of the excretion system for indoxyl sulfate causes its accumulation in blood. The purpose of the present study was to characterize the transport mechanism responsible for the renal excretion of indoxyl sulfate. Methods. The [3H]indoxyl sulfate transport mechanism was investigated using an in vivo tissue-sampling single-injection technique, the kidney uptake index (KUI) method. Rat organic anion transporter 3 (rOAT3)-expressing Xenopus laevis oocyte system was used for measuring [3H]indoxyl sulfate uptake activity. Results. Probenecid showed a concentration-dependent inhibitory effect on the uptake of [3H]indoxyl sulfate using the KUI method, and uptake was inhibited by organic anions such as para-aminohippuric acid (PAH) and benzylpenicillin, by weak base such as cimetidine, and by uremic toxins, such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) and hippuric acid (HA). However, salicylic acid, indomethacin, 3,5,3′-triiodo-L-thyronine and indole acetic acid (IA) had no effect on the uptake. rOAT3-expressing oocytes exhibited uptake of [3H]indoxyl sulfate by rOAT3 (Km= 158 μmol/L). Moreover, a number of uremic toxins inhibited the uptake of [3H]indoxyl sulfate by rOAT3. Conclusions. These results suggest that rOAT3 is responsible for the renal uptake of indoxyl sulfate, and uremic toxins share the transport mechanism for indoxyl sulfate. Mutual inhibition of these uremic toxins via OAT3 may accelerate their accumulation in the body and, thereby, the progression of nephrotoxicity in uremia.

Original languageEnglish
Pages (from-to)1760-1768
Number of pages9
JournalKidney international
Volume61
Issue number5
DOIs
Publication statusPublished - 2002

Keywords

  • Chronic renal failure
  • Indoxyl sulfate
  • Nephrotoxicity
  • Organic anion transporter 3
  • Renal disease
  • Uremia
  • Uremic toxin

ASJC Scopus subject areas

  • Nephrology

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