and p53 Cisplatin-Induced Renal Injury Is Independently Mediated by OCT2

Abstract Purpose: Tubular secretion of cisplatin is abolished in mice deficient for theorganic cation transportersOct1 and Oct2 (Oct1/2 / mice), and these animals are protected from severe cisplatin-induced kidneydamage. Since tubular necrosis is not completely absent in Oct1/2 / mice, we hypothesized that alternatepathways are involved in the observed injury.Experimental Design: Studies were done in wild-type, Oct1/2 / , or p53-deficient animals, all on anFVB background, receiving cisplatin intraperitoneally at 15 mg/kg. Cisplatin metabolites were analyzedusingmassspectrometry,andgeneexpressionwasassessedusingAffymetrixmicroarraysandRT-PCRarrays.Results: KEGG pathway analyses on kidneys from mice exposed to cisplatin revealed that the mostsignificantlyalteredgeneswereassociatedwiththep53signalingnetwork,includingCdnk1aandMdm2,inboth wild-type (P ¼ 2.40 10 11 ) and Oct1/2 / mice (P ¼ 1.92 10 8 ). This was confirmed bydemonstratingthathomozygosityforap53-nullallelepartiallyreducedrenaltubulardamage,whereaslossof p53 in Oct1/2