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Archives of Toxicology

, Volume 92, Issue 4, pp 1539–1550 | Cite as

Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation

  • Cyrille Vandenbussche
  • Cynthia Van der Hauwaert
  • Edmone Dewaeles
  • Jessica Franczak
  • Marie-Flore Hennino
  • Viviane Gnemmi
  • Grégoire Savary
  • Quentin Tavernier
  • Nicolas Nottet
  • Agnès Paquet
  • Michaël Perrais
  • David Blum
  • Bernard Mari
  • Nicolas Pottier
  • François Glowacki
  • Christelle Cauffiez
Organ Toxicity and Mechanisms
  • 344 Downloads

Abstract

Although Tacrolimus is an immunosuppressive drug widely used in renal transplantation, its chronic use paradoxically induces nephrotoxic effects, in particular renal fibrosis, which is responsible for chronic allograft dysfunction and represents a major prognostic factor of allograft survival. As molecular pathways and mechanisms involved in Tacrolimus-induced fibrogenic response are poorly elucidated, we assessed whether miRNAs are involved in the nephrotoxic effects mediated by Tacrolimus. Treatment of CD-1 mice with Tacrolimus (1 mg/kg/d for 28 days) resulted in kidney injury and was associated with alteration of a gene expression signature associated with cellular stress, fibrosis and inflammation. Tacrolimus also affected renal miRNA expression, including miRNAs previously involved in fibrotic and inflammatory processes as “fibromirs” such as miR-21-5p, miR-199a-5p and miR-214-3p. In agreement with in vivo data, Renal Proximal Tubular Epithelial cells exposed to Tacrolimus (25 and 50 µM) showed upregulation of miR-21-5p and the concomitant induction of epithelial phenotypic changes, inflammation and oxidative stress. In conclusion, this study suggests for the first time that miRNAs, especially fibromiRs, participate to Tacrolimus-induced nephrotoxic effects. Therefore, targeting miRNAs may be a new therapeutic option to counteract Tacrolimus deleterious effects on kidney.

Keywords

MicroRNA Tacrolimus Renal fibrosis Kidney injury 

Notes

Acknowledgements

The authors gratefully thank M-H Gevaert (Laboratoire d’Histologie, Faculté de Médecine de Lille) and D Taillieu (Animalerie Haute Technologie, Faculté de Médecine de Lille) for their technical help. The authors gratefully also acknowledge the technical support of V. Magnone, N. Pons, G. Rios (UCA GenomiX platform of the University Cote d’Azur).

Funding

This study was supported by Santelys association.

Supplementary material

204_2018_2158_MOESM1_ESM.docx (43 kb)
Supplementary material 1 (DOCX 42 KB)
204_2018_2158_MOESM2_ESM.docx (2.2 mb)
Supplementary material 2 (DOCX 2300 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Cyrille Vandenbussche
    • 1
    • 2
  • Cynthia Van der Hauwaert
    • 1
    • 3
  • Edmone Dewaeles
    • 1
  • Jessica Franczak
    • 1
  • Marie-Flore Hennino
    • 1
    • 2
  • Viviane Gnemmi
    • 4
    • 5
    • 6
  • Grégoire Savary
    • 1
    • 7
  • Quentin Tavernier
    • 1
  • Nicolas Nottet
    • 7
  • Agnès Paquet
    • 7
  • Michaël Perrais
    • 4
    • 5
  • David Blum
    • 4
    • 5
  • Bernard Mari
    • 7
  • Nicolas Pottier
    • 1
    • 8
  • François Glowacki
    • 1
    • 9
  • Christelle Cauffiez
    • 1
  1. 1.EA 4483-IMPECS-IMPact of Environmental ChemicalS on Human Health, Faculté de Médecine/Pôle RechercheUniv. LilleLille CedexFrance
  2. 2.Centre Hospitalier de Valenciennes-Service de Néphrologie, Médecine Interne et VasculaireValenciennesFrance
  3. 3.Département de la Recherche en SantéCHU LilleLilleFrance
  4. 4.UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre AUBERT Neurosciences et CancerUniv. LilleLilleFrance
  5. 5.UMR-S 1172InsermLilleFrance
  6. 6.Service d’AnatomopathologieCHU LilleLilleFrance
  7. 7.CNRS, IPMC, FHU-OncoAgeUniversité Côte d’AzurValbonneFrance
  8. 8.Service de Toxicologie et GénopathiesCHU LilleLilleFrance
  9. 9.Service de NéphrologieCHU LilleLilleFrance

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