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Arch Toxicol. 2018 Apr;92(4):1539-1550. doi: 10.1007/s00204-018-2158-3. Epub 2018 Jan 23.

Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation.

Author information

1
EA 4483-IMPECS-IMPact of Environmental ChemicalS on Human Health, Faculté de Médecine/Pôle Recherche, Univ. Lille, 1, place de Verdun, 59045, Lille Cedex, France.
2
Centre Hospitalier de Valenciennes-Service de Néphrologie, Médecine Interne et Vasculaire, 59300, Valenciennes, France.
3
Département de la Recherche en Santé, CHU Lille, 59000, Lille, France.
4
UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Univ. Lille, 59000, Lille, France.
5
UMR-S 1172, Inserm, 59000, Lille, France.
6
Service d'Anatomopathologie, CHU Lille, 59000, Lille, France.
7
CNRS, IPMC, FHU-OncoAge, Université Côte d'Azur, 06560, Valbonne, France.
8
Service de Toxicologie et Génopathies, CHU Lille, 59000, Lille, France.
9
Service de Néphrologie, CHU Lille, 59000, Lille, France.
10
EA 4483-IMPECS-IMPact of Environmental ChemicalS on Human Health, Faculté de Médecine/Pôle Recherche, Univ. Lille, 1, place de Verdun, 59045, Lille Cedex, France. christelle.cauffiez@univ-lille2.fr.

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:

Kidney injury; MicroRNA; Renal fibrosis; Tacrolimus

PMID:
29362864
DOI:
10.1007/s00204-018-2158-3

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