Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats.
OBJECTIVE
The purpose of this study was to examine the regulation of renal organic ion transporters in cisplatin-induced acute kidney injury (AKI) and its relation with indoxyl sulfate (IS), a uremic toxin.


METHODS
The IS concentrations in the serum and kidney were monitored by high-performance liquid chromatography. Uptake of p-aminohippuric acid, estrone-3-sulfate and tetraethylammonium were examined using renal slices. Real-time PCR and immunoblotting were performed to examine the mRNA and protein expression of rOATs, rOCTs and rMATE1 in the kidney, respectively.


RESULTS
The serum and renal IS levels were markedly elevated in cisplatin-treated rats. However, this effect was largely reversed by administration of AST-120, an oral charcoal adsorbent. The functions of renal basolateral organic anion and cation transporters were reduced in cisplatin-treated rats. The levels of mRNA and protein corresponding to rOAT1, rOAT3, rOCT2 and rMATE1, but not rOCT1, were depressed in the kidney of cisplatin-treated rats. Administration of AST-120 to cisplatin-treated rats partially restored the function and expression level of these transporters.


CONCLUSIONS
Cisplatin-induced AKI causes down-regulation of renal organic ion transporters accompanied by accumulation of serum and renal IS. IS could be involved in the mechanism of down-regulation of rOAT1, rOAT3 and rMATE1 under cisplatin-induced AKI.
Morisaki
Takafumi
T
Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Matsuzaki
Takanobu
T
Yokoo
Koji
K
Kusumoto
Masahiro
M
Iwata
Kazufumi
K
Hamada
Akinobu
A
Saito
Hideyuki
H
D000208:Acute Disease; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017920:Antiporters / Q000235:genetics; D002244:Carbon / Q000494:pharmacology; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000235:genetics; D002945:Cisplatin / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D007200:Indican / Q000032:analysis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D010087:Oxides / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014511:Uremia / Q000139:chemically induced* / Q000378:metabolism
D000970:Antineoplastic Agents; D017920:Antiporters; D050482:Catecholamine Plasma Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D010087:Oxides; D012333:RNA, Messenger; C493212:Slc22a1 protein, rat; C100590:Slc22a2 protein, rat; C421043:Slc22a6 protein, rat; C515734:Slc47a1 protein, rat; C114338:organic anion transport protein 3; D002244:Carbon; C040896:AST 120; D007200:Indican; D002945:Cisplatin