Cyclosporine A (CsA), a widely used immunosuppressive drug in organ transplantation and autoimmune disorders, frequently induces renal damage and fibrosis. Recent evidence has implicated epithelial-mesenchymal transition (EMT) in CsA-induced nephrotoxicity. Microarray analysis disclosed miR-181c as the microRNA most dramatically repressed by CsA. Downregulation of miR-181c expression at the transcriptional level by CsA is dependent on the transcription factor Nrf2. miR-181c mimics or inhibitors attenuate or aggravate CsA-induced EMT gene changes, respectively. Importantly, in Nrf2-/- mice, CsA-induced renal damage, fibrosis, and EMT gene changes are restored by miR-181c mimics. Mechanistically, we identified Notch2 as a potential target of miR-181c. Collectively, our data support the notion that miR-181c may serve as an important factor for protecting renal tissues from CsA-induced nephrotoxicity.
Keywords: Nrf2; cyclosporine A; epithelial-mesenchymal transition; fibrosis; miR-181c.
© 2017 Federation of European Biochemical Societies.