title: Organic anion transporters play an important role in the uptake of p-cresyl sulfate, a uremic toxin, in the kidney.
abstract: BACKGROUND
  p-Cresyl sulfate (PCS), a recently identified anionic uremic toxin, is the main circulating metabolite of p-cresol. In cases of chronic kidney disease (CKD), it might be associated with cardiovascular outcomes and the progression of CKD. However, the renal excretion pathway of PCS is currently unknown. The objective of the present study was to determine whether organic anion transporters (OATs), which are renal tubular basolateral membrane transporters, play an important role in this process.
  
  
  METHODS
  The uptake of PCS was investigated using rat renal cortical slices and human proximal tubular cells (HK-2). The active uptake velocity was calculated by subtracting the uptake velocity at 4°C (nonspecific uptake) from that at 37°C.
  
  
  RESULTS
  As evidenced by renal cortical slice experiments, the uptake of PCS was saturable with a mean K(m) of 231.6 μM, indicating that the active transport is involved in the basolateral uptake of PCS. Similar results were also observed in HK-2 cells. The active transport of PCS was significantly suppressed by inhibitors of OATs, such as probenecid, benzylpenicillin, p-aminohippuric acid and estrone sulfate. Similar inhibitions were observed in the presence of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropionate, OATs substrates among uremic toxins. In contrast, digoxin and tetraethylammonium that did not interact with OATs had little inhibitory effect.
  
  
  CONCLUSIONS
  The findings of the present study strongly suggest that PCS serves as a substrate for OATs, is preferentially recognized by OAT3 and plays a key role in the renal tubular secretion process.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Noguchi
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kotani
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakajima
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kadowaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003408:Cresols / Q000378:metabolism*; D006801:Humans; D007672:Kidney Cortex / Q000166:cytology / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013463:Sulfuric Acid Esters / Q000378:metabolism*; D014118:Toxins, Biological / Q000378:metabolism*
chemical_list: D003408:Cresols; D027361:Organic Anion Transporters; D013463:Sulfuric Acid Esters; D014118:Toxins, Biological; C408690:4-cresol sulfate