Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation
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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.
KeywordsMicroRNA Tacrolimus Renal fibrosis Kidney injury
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).
This study was supported by Santelys association.
- Baxter RM, Crowell TP, George JA et al (2007) The plant pathogenesis related protein GLIPR-2 is highly expressed in fibrotic kidney and promotes epithelial to mesenchymal transition in vitro. Matrix Biol J Int Soc Matrix Biol 26:20–29. https://doi.org/10.1016/j.matbio.2006.09.005 CrossRefGoogle Scholar
- Castro NE, Kato M, Park JT, Natarajan R (2014) Transforming growth factor b1 (TGF-b1) enhances expression of profibrotic genes through a novel signaling cascade and microRNAs in renal mesangial cells. J Biol Chem 289:29001–29013. https://doi.org/10.1074/jbc.M114.600783 CrossRefPubMedPubMedCentralGoogle Scholar
- Ding L, Karanam NK, Yordy JS, Giri U, Story MD (2015) miRNA associated with distal metastasis and local recurrence after postoperative radiotherapy in high-risk head and neck cancer 75(15) https://doi.org/10.1158/1538-7445.AM2015-3998 (Abstract 3998)
- Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu Rev Med 57:365–380. https://doi.org/10.1146/annurev.med.57.121304.131342 CrossRefPubMedGoogle Scholar
- Martin-Martin N, Ryan G, McMorrow T, Ryan MP (2010) Sirolimus and cyclosporine A alter barrier function in renal proximal tubular cells through stimulation of ERK1/2 signaling and claudin-1 expression. Am J Physiol Renal Physiol 298:F672-682. https://doi.org/10.1152/ajprenal.00199.2009 CrossRefGoogle Scholar
- Snanoudj R, Royal V, Elie C et al (2011) Specificity of histological markers of long-term CNI nephrotoxicity in kidney-transplant recipients under low-dose cyclosporine therapy: histological signs of CNI toxicity. Am J Transplant 11:2635–2646. https://doi.org/10.1111/j.1600-6143.2011.03718.x CrossRefPubMedGoogle Scholar
- Xiong M, Jiang L, Zhou Y et al (2012) The miR-200 family regulates TGF-b1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression. Am J Physiol Renal Physiol 302:F369-379. https://doi.org/10.1152/ajprenal.00268.2011 CrossRefGoogle Scholar
- Yuan J, Benway CJ, Bagley J, Iacomini J (2015) MicroRNA-494 promotes cyclosporine-induced nephrotoxicity and epithelial to mesenchymal transition by inhibiting PTEN: MicroRNAs and cyclosporine nephrotoxicity. Am J Transplant 15:1682–1691. https://doi.org/10.1111/ajt.13161 CrossRefPubMedGoogle Scholar