title: MicroRNA-494 promotes cyclosporine-induced nephrotoxicity and epithelial to mesenchymal transition by inhibiting PTEN.
abstract: A major complication associated with cyclosporine (CsA) treatment is nephrotoxicity. In this study, we examined whether microRNAs play a role in cyclosporine-induced nephrotoxicity. Treatment of mice with CsA resulted in nephrotoxicity that was associated with an early increase in expression of microRNA mmu-miR-494 (miR-494). Similarly, tubular epithelial cell epithelial-mesenchymal transition (EMT) induced by CsA toxicity resulted in the upregulation of microRNA-494 and a decrease in PTEN levels in vitro. miR-494 directly targeted Pten and negatively regulated its expression. Preventing Pten targeting by miR-494 was sufficient to prevent CsA induced EMT. Knockdown of miR-494 prevented the downregulation of PTEN in tubular epithelial cells following CsA treatment and also prevented CsA induced EMT. Thus, miR-494 plays a major role in promoting CsA induced nephrotoxicity through its ability to target Pten thereby contributing to EMT. We suggest that manipulating miR-494 expression may represent a novel approach to preventing EMT associated with CsA induced nephrotoxicity.
authors: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA.
authors: J
authors: J
authors: Yuan
authors: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA.|Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Boston, MA.
authors: C J
authors: CJ
authors: Benway
authors: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA.
authors: J
authors: J
authors: Bagley
authors: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA.|Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Boston, MA.
authors: J
authors: J
authors: Iacomini
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D023421:Models, Animal; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D035683:MicroRNAs; C550178:Mirn494 microRNA, mouse; D016572:Cyclosporine; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: basic (laboratory) research/science; calcineurin inhibitor: cyclosporine A (CsA); complication; drug toxicity; immunosuppressant; immunosuppression/immune modulation; kidney failure/injury; kidney transplantation/nephrology; molecular biology: micro RNA; translational research/science