title: Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity.
abstract: In uremic patients, various uremic toxins are accumulated and exert various biologic effects on uremia. Indoxyl sulfate (IS) is one of uremic toxins that is derived from dietary protein, and serum levels of IS are markedly increased in both uremic rats and patients. It has been previously reported that the accumulation of IS promotes the progression of chronic renal failure (CRF). This study demonstrates the role of rat organic anion transporters (rOATs) in the transport of IS and the induction of its nephrotoxicity. The administration of IS to 5/6-nephrectomized rats caused a faster progression of CRF, and immunohistochemistry revealed that IS was detected in the proximal and distal tubules where rOAT1 (proximal tubules) and/or rOAT3 (proximal and distal tubules) were also shown to be localized. In in vitro study, the proximal tubular cells derived from mouse that stably express rOAT1 (S2 rOAT1) and rOAT3 (S2 rOAT3) were established. IS inhibited organic anion uptake by S2 rOAT1 and S2 rOAT3, and the Ki values were 34.2 and 74.4 microM, respectively. Compared with mock, S2 rOAT1 and S2 rOAT3 exhibited higher levels of IS uptake, which was inhibited by probenecid and cilastatin, organic anion transport inhibitors. The addition of IS induced a decrease in the viability of S2 rOAT1 and S2 rOAT3 as compared with the mock, which was rescued by probenecid. These results suggest that rOAT1 and rOAT3 play an important role in the transcellular transport of IS and the induction of its nephrotoxicity.
authors.affiliation: Department of Clinical Preventive Medicine, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.forename: Michio
authors.initials: M
authors.lastname: Takeda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tojo
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekine
authors.forename: Seok Ho
authors.initials: SH
authors.lastname: Cha
authors.forename: Suparat
authors.initials: S
authors.lastname: Khamdang
authors.forename: Fumio
authors.initials: F
authors.lastname: Takayama
authors.forename: Isao
authors.initials: I
authors.lastname: Aoyama
authors.forename: Sakurako
authors.initials: S
authors.lastname: Nakamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Niwa
mesh_terms: D000818:Animals; D000838:Anions / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D007150:Immunohistochemistry; D007200:Indican / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology*; D007684:Kidney Tubules / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology; D051379:Mice; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D009994:Osmolar Concentration; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000838:Anions; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D007200:Indican; D011339:Probenecid