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

• Published in: Clinical cancer research Vol. 20; no. 15; pp. 4026 - 4035
• Main Authors: SPROWL, Jason A, LANCASTER, Cynthia S, CIARIMBOLI, Giuliano, SPARREBOOM, Alex, PABLA, Navjotsingh, HERMANN, Edwin, KOSLOSKE, Ashley M, GIBSON, Alice A, LIE LI, ZEEH, Dorothea, SCHLATTER, Eberhard, JANKE, Laura J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2014
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - metabolism; Antineoplastic Agents - toxicity; Benzothiazoles - pharmacology; Biological and medical sciences; Biomarkers - metabolism; Cisplatin - metabolism; Cisplatin - toxicity; Female; Gene Expression Profiling; Homeodomain Proteins - metabolism; Kidney Diseases - chemically induced; Kidney Diseases - pathology; Kidney Diseases - prevention & control; Male; Medical sciences; Mice; Mice, Knockout; Octamer Transcription Factor-1 - antagonists & inhibitors; Octamer Transcription Factor-1 - physiology; Oligonucleotide Array Sequence Analysis; Organic Cation Transport Proteins - antagonists & inhibitors; Organic Cation Transport Proteins - physiology; Organic Cation Transporter 2; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Toluene - analogs & derivatives; Toluene - pharmacology; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - physiology; Antineoplastic agent; Alkylating agent; TP53 Gene; Urinary system; Toxicity; Transcription factor Oct2; Cisplatin; Kidney; Platinum II Complexes; Tumor suppressor gene
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-14-0319

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. 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. 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. 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.