Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling

Jianguo Chen, Anna Zmijewska, Degui Zhi, Roslyn B. Mannon

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Calcineurin inhibitors (CNIs) are potent immunosuppressants with associated long-term nephrotoxicity mediated by tubular epithelial cell injury and arterial vasoconstriction. We hypothesized that CNI-induced renal injury is regulated by specific microRNAs (miRNAs). In this study, we found that 46 miRNAs were significantly altered in human proximal tubular epithelial cells (HPTECs) following exposure to cyclosporine A (CsA), particularly miR-21 (5.47 ± 0.47-fold versus vehicle, P = 0.002). This increase was accompanied by alterations in epithelial-mesenchymal transformation (EMT) markers including vimentin (2.80 ± 0.28-fold; P = 0.03), S100A4 (2.29 ± 0.29-fold; P = 0.04), and α-SMA (5.0 ± 0.31-fold; P = 0.03). Notably, transfection of HPTECs with miR-21 precursor also resulted in significant induction of EMT-associated genes, which were inhibited by a single-stranded nucleic acid inhibitor of miR-21. miR-21 induction resulted in a rapid increase of phosphorylated AKT and downregulation of PTEN. While CsA induces SMAD7 downregulation and TGF-β1 upregulation in HPTECs, such changes were independent of miR-21. Moreover, there was no effect on ERK phosphorylation. We confirmed these changes using a mouse model of CsA toxicity. Collectively, our results suggest that miR-21 mediates CsA nephrotoxicity via PTEN/AKT signaling pathway. Further exploration into the epigenetic response to CsA exposure may provide new therapeutic targets to ameliorate CsA nephrotoxicity.

Original languageEnglish (US)
Pages (from-to)232-245
Number of pages14
JournalTransplant International
Volume28
Issue number2
DOIs
StatePublished - Feb 1 2015

Keywords

  • cyclosporine
  • fibrosis
  • microRNA
  • nephrotoxicity
  • signaling
  • transplantation

ASJC Scopus subject areas

  • Transplantation

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