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An integrative approach to cisplatin chronic toxicities in mice reveals importance of organic cation-transporter-dependent protein networks for renoprotection

  • Toxicokinetics and Metabolism
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Abstract

Cisplatin (CDDP) is one of the most important chemotherapeutic drugs in modern oncology. However, its use is limited by severe toxicities, which impair life quality after cancer. Here, we investigated the role of organic cation transporters (OCT) in mediating toxicities associated with chronic (twice the week for 4 weeks) low-dose (4 mg/kg body weight) CDDP treatment (resembling therapeutic protocols in patients) of wild-type (WT) mice and mice with OCT genetic deletion (OCT1/2−/−). Functional and molecular analysis showed that OCT1/2−/− mice are partially protected from CDDP-induced nephrotoxicity and peripheral neurotoxicity, whereas ototoxicity was not detectable. Surprisingly, proteomic analysis of the kidneys demonstrated that genetic deletion of OCT1/2 itself was associated with significant changes in expression of proinflammatory and profibrotic proteins which are part of an OCT-associated protein network. This signature directly regulated by OCT consisted of three classes of proteins, viz., profibrotic proteins, proinflammatory proteins, and nutrient sensing molecules. Consistent with functional protection, CDDP-induced proteome changes were more severe in WT mice than in OCT1/2−/− mice. Laser ablation-inductively coupled plasma-mass spectrometry analysis demonstrated that the presence of OCT was not associated with higher renal platinum concentrations. Taken together, these results redefine the role of OCT from passive membrane transporters to active modulators of cell signaling in the kidney.

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Acknowledgements

The authors are grateful to Dr Massimo Zucchetti from the Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy, for the platinum determination in neuronal tissues. This study was supported by the Deutsche Forschungsgemeinschaft (CI 107/11-1 to MMR, AaZD, and GiC), and in part by National Institutes of Health grants (R01CA215802 to AS), and for the neurotoxicity part by a research grant from “Fondazione Banca del Monte di Lombardia” to PM.

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Authors and Affiliations

  1. Medizinische Klinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1/A14, 48149, Münster, Germany

    Anna Hucke, Rita Schröter, Eberhard Schlatter, Hermann Pavenstädt, Vivien Barz & Giuliano Ciarimboli

  2. Department II of Internal Medicine, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    Markus M. Rinschen

  3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Markus M. Rinschen

  4. Institut für Anorganische und Analytische Chemie, Westfälische Wilhelms-Universität, Münster, Germany

    Oliver B. Bauer, Michael Sperling, Uwe Karst, Christina Köppen & Karolin Sommer

  5. Experimental Neurology Unit of the Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy

    Cecilia Ceresa, Alessia Chiorazzi, Annalisa Canta, Sara Semperboni, Paola Marmiroli & Guido Cavaletti

  6. Centrum für Reproduktionsmedizin und Andrologie, Universitätsklinikum Münster, Münster, Germany

    Stefan Schlatt

  7. Gerhard-Domagk-Institut für Pathologie, Universitätsklinikum Münster, Münster, Germany

    Barbara Heitplatz & Veerle Van Marck

  8. Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    Alex Sparreboom

  9. Klinik für Phoniatrie und Pädaudiologie, Universitätsklinikum Münster, Münster, Germany

    Arne Knief, Dirk Deuster & Antoinette am Zehnhoff-Dinnesen

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  1. Anna Hucke
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Contributions

Planned the study: UK, MS, GuC, StS, ES, HP, AS, AaZD, and GiC. Performed the experiments: AH, MMR, OBB, CK, KS, RS, CC, AlC, AnC, SaS, PM, VB, AK, DD, and GiC. Performed histological analysis: BH and VVM. Wrote the manuscript: UK, GuC, CC, HP, AS, AaZD, and GiC.

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Correspondence to Giuliano Ciarimboli.

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204_2019_2557_MOESM1_ESM.docx

This chapter contains technical details of experiments. Moreover, the body weight of the mice during the experiments (suppl. Material Fig. 1), a part of results of histopathological analysis of the kidney (suppl. Material Fig. 2), T-cells infiltration into the kidneys (suppl. Material Fig. 3), and the Pt content of different tissues (suppl. Material Fig. 4) are also shown. This section contains also the primer sequences (suppl. Material Table 1), and the detailed results of proteomic analysis (suppl. Material Table 2). (DOCX 7968 kb)

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Hucke, A., Rinschen, M.M., Bauer, O.B. et al. An integrative approach to cisplatin chronic toxicities in mice reveals importance of organic cation-transporter-dependent protein networks for renoprotection. Arch Toxicol 93, 2835–2848 (2019). https://doi.org/10.1007/s00204-019-02557-9

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