Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney.
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 micromol/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.
Deguchi
Tsuneo
T
Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Ohtsuki
Sumio
S
Otagiri
Masaki
M
Takanaga
Hitomi
H
Asaba
Hiroshi
H
Mori
Shinobu
S
Terasaki
Tetsuya
T
D000818:Animals; D000838:Anions / Q000493:pharmacokinetics; D001692:Biological Transport / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000493:pharmacokinetics; D007200:Indican / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008297:Male; D009865:Oocytes / Q000502:physiology; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D011422:Propionates / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014118:Toxins, Biological / Q000493:pharmacokinetics; D014316:Tritium; D014511:Uremia / Q000378:metabolism; D014528:Uricosuric Agents / Q000494:pharmacology; D014982:Xenopus laevis; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
D000838:Anions; D005663:Furans; D029362:Organic Anion Transporters, Sodium-Independent; D011422:Propionates; C421143:Slco1a5 protein, rat; D014118:Toxins, Biological; D014528:Uricosuric Agents; D014316:Tritium; C041693:3-carboxy-4-methyl-5-propyl-2-furanpropionic acid; D007200:Indican; D011339:Probenecid; D010130:p-Aminohippuric Acid