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

Authors:
  • JSJason A. Sprowl
    Jason A. Sprowl
  • CLCynthia S. Lancaster
    Cynthia S. Lancaster
  • NPNavjotsingh Pabla
    Navjotsingh Pabla
  • EHEdwin Hermann
    Edwin Hermann
  • AKAshley M. Kosloske
    Ashley M. Kosloske
  • AGAlice A. Gibson
    Alice A. Gibson
  • LLLie Li
    Lie Li
  • DZDorothea Zeeh
    Dorothea Zeeh
  • ESEberhard Schlatter
    Eberhard Schlatter
  • LJLaura J. Janke
    Laura J. Janke
  • GCGiuliano Ciarimboli
    Giuliano Ciarimboli
  • ASAlex Sparreboom
    Alex Sparreboom
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Abstract
Purpose: 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.Experimental Design: 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. Clin Cancer Res; 20(15); 4026–35. ©2014 AACR.