Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation [transcriptome analysis]

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 (1mg/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 including “fibromirs” such as miR-21-5p. Specifically, Renal Proximal Tubular Epithelial cells exposed to tacrolimus showed up-regulation 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, mediate Tacrolimus-induced nephrotoxic effects. CD-1 mice were treated with Tacrolimus (1mg/kg/d for 28 days) or physiological serum as control (n=4) and total RNA was prepared from kidneys. Experiment performed in a one color design, corresponding to 2 conditions (Control: CTL and Tacrolimus: TAC) for a total of 8 samples.