Hucke, Anna, Rinschen, Markus M., Bauer, Oliver B., Sperling, Michael ORCID: 0000-0001-6676-2487, Karst, Uwe, Koeppen, Christina, Sommer, Karolin, Schroeter, Rita, Ceresa, Cecilia, Chiorazzi, Alessia ORCID: 0000-0002-3469-1829, Canta, Annalisa, Semperboni, Sara, Marmiroli, Paola, Cavaletti, Guido, Schlatt, Stefan, Schlatter, Eberhard, Pavenstaedt, Hermann, Heitplatz, Barbara, Van Marck, Veerle, Sparreboom, Alex, Barz, Vivien, Knief, Arne, Deuster, Dirk, Zehnhoff-Dinnesen, Antoinette Am and Ciarimboli, Giuliano (2019). An integrative approach to cisplatin chronic toxicities in mice reveals importance of organic cation-transporter-dependent protein networks for renoprotection. Arch. Toxicol., 93 (10). S. 2835 - 2849. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hucke, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bauer, Oliver B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sperling, MichaelUNSPECIFIEDorcid.org/0000-0001-6676-2487UNSPECIFIED
Karst, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeppen, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sommer, KarolinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeter, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ceresa, CeciliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chiorazzi, AlessiaUNSPECIFIEDorcid.org/0000-0002-3469-1829UNSPECIFIED
Canta, AnnalisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Semperboni, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marmiroli, PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cavaletti, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlatt, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlatter, EberhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pavenstaedt, HermannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heitplatz, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Marck, VeerleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sparreboom, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barz, VivienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knief, ArneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deuster, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zehnhoff-Dinnesen, Antoinette AmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ciarimboli, GiulianoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-132588
DOI: 10.1007/s00204-019-02557-9
Journal or Publication Title: Arch. Toxicol.
Volume: 93
Number: 10
Page Range: S. 2835 - 2849
Date: 2019
Publisher: SPRINGER HEIDELBERG
Place of Publication: HEIDELBERG
ISSN: 1432-0738
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PLATINUM RESISTANCE; KIDNEY; NEPHROTOXICITY; MECHANISMS; EXTRACTION; PROTEOMICS; SECRETION; MODELSMultiple languages
ToxicologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13258

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