Renal xenobiotic transporters are differentially expressed in mice following cisplatin treatment.
The goal of this study was to identify alterations in mRNA and protein expression of various xenobiotic transport proteins in mouse kidney during cisplatin-induced acute renal failure. For this purpose, male C57BL/6J mice received a single dose of cisplatin (18 mg/kg, i.p.) or vehicle. Four days later, tissues were collected for assessment of plasma BUN, histopathological analysis of renal lesions, and mRNA and Western blot analysis of renal transporters including organic anion and cation transporters (Oat, Oct), organic anion transporting polypeptides (Oatp), multidrug resistance-associated proteins (Mrp), multidrug resistance proteins (Mdr), breast cancer resistance protein (Bcrp) and multidrug and toxin extrusion proteins (Mate). Cisplatin treatment caused necrosis of renal proximal tubules along with elevated plasma BUN and renal kidney injury molecule-1 mRNA expression. Cisplatin-induced renal injury increased mRNA and protein levels of the efflux transporters Mrp2, Mrp4, Mrp5, Mdr1a and Mdr1b. Uptake transporters Oatp2a1 and Oatp2b1 mRNA were also up-regulated following cisplatin. By contrast, expression of Oat1, Oat2, Oct2 and Oatp1a1 mRNA was reduced in cisplatin-treated mice. Expression of several uptake and efflux transporters was unchanged in cisplatin-treated mice. Apical staining of Mrp2 and Mrp4 proteins was enhanced in proximal tubules from cisplatin-treated mice. Collectively, these expression patterns suggest coordinated regulation of uptake and efflux pathways during cisplatin-induced renal injury. Reduced expression of basolateral and apical uptake transporters along with enhanced transcription of export transporters likely represents an adaptation to lower intracellular accumulation of chemicals, prevent their reabsorption and enhance urinary clearance.
Aleksunes
Lauren M
LM
University of Connecticut, Department of Pharmaceutical Sciences, 69 North Eagleville Road, U-3092 Storrs, CT 06269-3092, United States. lauren.aleksunes@gmail.com
Augustine
Lisa M
LM
Scheffer
George L
GL
Cherrington
Nathan J
NJ
Manautou
José E
JE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D021121:Branched DNA Signal Amplification Assay; D002352:Carrier Proteins / Q000096:biosynthesis*; D002945:Cisplatin / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D004364:Pharmaceutical Preparations / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D015262:Xenobiotics / Q000378:metabolism*
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004364:Pharmaceutical Preparations; D015262:Xenobiotics; D012313:RNA; D002945:Cisplatin