Enhanced renal accumulation of cisplatin via renal organic cation transporter deteriorates acute kidney injury in hypomagnesemic rats.
BACKGROUND
This study aimed to explore the effects of hypomagnesemia on cisplatin (CDDP)-induced acute kidney injury (AKI) in rats and the relation of hypomagnesemia to the regulation of organic cation transporters and renal accumulation of CDDP.


METHODS
Sprague-Dawley rats were given an Mg-deficient diet starting 7 days before treatment with CDDP. CDDP was administered intravenously to rats in the normal Mg-diet group and Mg-deficient-diet group at 3 mg/kg via the left jugular vein. At the specified periods after injection of CDDP, the amount of platinum in blood and organ samples was determined using inductively coupled plasma-mass spectrometry. Protein expression levels of renal organic cation transporters were determined. Uptake of tetraethylammonium (TEA) bromide in renal slices of rats was measured.


RESULTS
Rats fed a Mg-deficient diet showed a significant body weight decrease and a marked decrease in serum Mg levels compared with control rats fed an adequate Mg diet. Serum blood urea nitrogen and creatinine levels were unaltered after CDDP treatment in control rats, whereas these levels were markedly elevated in hypomagnesemic rats. Immunoblotting revealed up-regulation of the organic cation transporter rOCT2 in hypomagnesemic rats before CDDP administration, but not of rOCT1 or rat multidrug and toxin-extrusion 1. TEA uptake by renal slices from hypomagnesemic rats was significantly higher compared with that of control rats. Renal accumulation of CDDP was markedly increased in hypomagnesemic rats.


CONCLUSIONS
These results suggest that hypomagnesemia could cause dehydration and up-regulation of rOCT2, enhancing renal accumulation of CDDP and the deterioration of AKI.
Yokoo
Koji
K
Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi, Kumamoto, Japan.
Murakami
Risa
R
Matsuzaki
Takanobu
T
Yoshitome
Kanako
K
Hamada
Akinobu
A
Saito
Hideyuki
H
D058186:Acute Kidney Injury / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D017920:Antiporters / Q000378:metabolism; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D002945:Cisplatin / Q000009:adverse effects / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008274:Magnesium / Q000097:blood; D008275:Magnesium Deficiency / Q000097:blood / Q000503:physiopathology*; D008297:Male; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D017920:Antiporters; D050482:Catecholamine Plasma Membrane Transport Proteins; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C493212:Slc22a1 protein, rat; C100590:Slc22a2 protein, rat; C515734:Slc47a1 protein, rat; D008274:Magnesium; D002945:Cisplatin