title: Cisplatin-induced renal injury is independently mediated by OCT2 and p53.
abstract: OBJECTIVE
  Tubular secretion of cisplatin is abolished in mice deficient for the organic cation transporters Oct1 and Oct2 (Oct1/2(-/-)mice), and these animals are protected from severe cisplatin-induced kidney damage. Since tubular necrosis is not completely absent in Oct1/2(-/-)mice, we hypothesized that alternate pathways are involved in the observed injury.
  
  
  METHODS
  Studies were done in wild-type, Oct1/2(-/-), or p53-deficient animals, all on an FVB background, receiving cisplatin intraperitoneally at 15 mg/kg. Cisplatin metabolites were analyzed using mass spectrometry, and gene expression was assessed using Affymetrix microarrays and RT-PCR arrays.
  
  
  RESULTS
  KEGG pathway analyses on kidneys from mice exposed to cisplatin revealed that the most significantly altered genes were associated with the p53 signaling network, including Cdnk1a and Mdm2, in both wild-type (P = 2.40 × 10(-11)) and Oct1/2(-/-)mice (P = 1.92 × 10(-8)). This was confirmed by demonstrating that homozygosity for a p53-null allele partially reduced renal tubular damage, whereas loss of p53 in Oct1/2(-/-)mice (p53(-/-)/Oct1/2(-/-)) completely abolished nephrotoxicity. We found that pifithrin-α, an inhibitor of p53-dependent transcriptional activation, inhibits Oct2 and can mimic the lack of nephrotoxicity observed in p53(-/-)/Oct1/2(-/-)mice.
  
  
  CONCLUSIONS
  These findings indicate that (i) the p53 pathway plays a crucial role in the kidney in response to cisplatin treatment and (ii) clinical exploration of OCT2 inhibitors may not lead to complete nephroprotection unless the p53 pathway is simultaneously antagonized.
authors.affiliation: Departments of Pharmaceutical Sciences and.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Sprowl
authors.affiliation: Departments of Pharmaceutical Sciences and.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Lancaster
authors.affiliation: Departments of Pharmaceutical Sciences and.
authors.forename: Navjotsingh
authors.initials: N
authors.lastname: Pabla
authors.affiliation: Klinik für Urologie and.
authors.forename: Edwin
authors.initials: E
authors.lastname: Hermann
authors.affiliation: Departments of Pharmaceutical Sciences and.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Kosloske
authors.affiliation: Departments of Pharmaceutical Sciences and.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Departments of Pharmaceutical Sciences and.
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.affiliation: Medizinische Klinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Münster, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Zeeh
authors.affiliation: Medizinische Klinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Münster, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlatter
authors.affiliation: Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee; and.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Janke
authors.affiliation: Medizinische Klinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Münster, Germany.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciarimboli
authors.affiliation: Departments of Pharmaceutical Sciences and alex.sparreboom@stjude.org.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D052160:Benzothiazoles / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050811:Octamer Transcription Factor-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D015415:Biomarkers; C098513:Gsh1 protein, mouse; C109498:Gsh2 protein, mouse; D018398:Homeodomain Proteins; D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C494166:Pou2f1 protein, mouse; D012333:RNA, Messenger; C491012:Slc22a2 protein, mouse; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; D002945:Cisplatin