期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 15, 期 6, 页码 1682-1691出版社
WILEY-BLACKWELL
DOI: 10.1111/ajt.13161
关键词
basic (laboratory) research; science; translational research; science; kidney transplantation; nephrology; immunosuppression; immune modulation; complication; drug toxicity; immunosuppressant; calcineurin inhibitor: cyclosporine A (CsA); kidney failure; injury; molecular biology: micro RNA
资金
- Roche Organ Transplantation Research Foundation
- American Heart Association Scientist Development Grant
- American Society of Transplantation/Genentech Basic Science Fellowship Grant
- NIH [R01AI83459-05]
- NIH Institutional Training Grant [T32AI070085]
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.
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