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

  • Anna Hucke
  • Markus M. Rinschen
  • Oliver B. Bauer
  • Michael Sperling
  • Uwe Karst
  • Christina Köppen
  • Karolin Sommer
  • Rita Schröter
  • Cecilia Ceresa
  • Alessia Chiorazzi
  • Annalisa Canta
  • Sara Semperboni
  • Paola Marmiroli
  • Guido Cavaletti
  • Stefan Schlatt
  • Eberhard Schlatter
  • Hermann Pavenstädt
  • Barbara Heitplatz
  • Veerle Van Marck
  • Alex Sparreboom
  • Vivien Barz
  • Arne Knief
  • Dirk Deuster
  • Antoinette am Zehnhoff-Dinnesen
  • Giuliano CiarimboliEmail author
Toxicokinetics and Metabolism
  • 92 Downloads

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.

Keywords

Cisplatin Toxicities Transporters Mouse model 

Notes

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.

Author 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.

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interests exists.

Ethical approval

The manuscript does not contain clinical studies or patient data.

Supplementary material

204_2019_2557_MOESM1_ESM.docx (7.8 mb)
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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Anna Hucke
    • 1
  • Markus M. Rinschen
    • 2
    • 3
  • Oliver B. Bauer
    • 4
  • Michael Sperling
    • 4
  • Uwe Karst
    • 4
  • Christina Köppen
    • 4
  • Karolin Sommer
    • 4
  • Rita Schröter
    • 1
  • Cecilia Ceresa
    • 5
  • Alessia Chiorazzi
    • 5
  • Annalisa Canta
    • 5
  • Sara Semperboni
    • 5
  • Paola Marmiroli
    • 5
  • Guido Cavaletti
    • 5
  • Stefan Schlatt
    • 6
  • Eberhard Schlatter
    • 1
  • Hermann Pavenstädt
    • 1
  • Barbara Heitplatz
    • 7
  • Veerle Van Marck
    • 7
  • Alex Sparreboom
    • 8
  • Vivien Barz
    • 1
  • Arne Knief
    • 9
  • Dirk Deuster
    • 9
  • Antoinette am Zehnhoff-Dinnesen
    • 9
  • Giuliano Ciarimboli
    • 1
    Email author
  1. 1.Medizinische Klinik D, Experimentelle NephrologieUniversitätsklinikum MünsterMünsterGermany
  2. 2.Department II of Internal Medicine, and Center for Molecular Medicine CologneUniversity of CologneCologneGermany
  3. 3.Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)University of CologneCologneGermany
  4. 4.Institut für Anorganische und Analytische ChemieWestfälische Wilhelms-UniversitätMünsterGermany
  5. 5.Experimental Neurology Unit of the Department of Medicine and SurgeryUniversity of Milano BicoccaMonzaItaly
  6. 6.Centrum für Reproduktionsmedizin und AndrologieUniversitätsklinikum MünsterMünsterGermany
  7. 7.Gerhard-Domagk-Institut für PathologieUniversitätsklinikum MünsterMünsterGermany
  8. 8.Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer CenterThe Ohio State UniversityColumbusUSA
  9. 9.Klinik für Phoniatrie und Pädaudiologie, Universitätsklinikum MünsterMünsterGermany

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