microRNA-494 Promotes Cyclosporine-Induced Nephrotoxicity and Epithelial to Mesenchymal Transition By Inhibiting PTEN
1Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA
2Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Tufts University School of Medicine, Boston, MA.
Meeting: 2015 American Transplant Congress
Abstract number: A242
Keywords: Fibrosis, Immunosuppression, Nephrotoxicity
Session Information
Session Name: Poster Session A: Preclinical Immunosuppression and Tolerance
Session Type: Poster Session
Date: Saturday, May 2, 2015
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Exhibit Hall E
Purpose: A major complication associated with cyclosporine (CsA) treatment is nephrotoxicity. MicroRNAs (miRs) have been shown to play an important role in various pathological conditions, including renal fibrosis and acute kidney injury. Thus, we examined whether microRNAs play a role in cyclosporine-induced nephrotoxicity.
Methods: C57BL/6 mice were treated with vehicle (olive oil), 10mg/kg CsA, 30mg/kg CsA or 50mg/kg CsA for 4 weeks to induce nephropathy.(n=4-5 per group) Periodic acid Schiff (PAS) stained slides were used to evaluate pathological changes in the kidneys. Expression of microRNA-494 (miR-494) was detected in the kidneys through realtime-PCR. Expressions of α-SMA and FSP-1 were determined by IHC. Western Blotting was used to analyze expression of PTEN and E-cadherin in the kidneys. In vitro, HK-2 cells were cultured in the presence of cyslosporine for up to 72 hours. Expressions of miR-494, PTEN, α-SMA and FSP-1 were detected via realtime-PCR, Western blotting, and immunofluorescence staining respectively. The ability of miR-494 to target Pten was verified via luciferase assay.
Results: Treatment of mice with CsA resulted in nephrotoxicity that was associated with an early increase in expression of miR-494. Similarly, tubular epithelial cell epithelial-mesenchymal transition (EMT) induced by CsA toxicity resulted in the up-regulation of microRNA-494. 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 down-regulation of PTEN in tubular epithelial cells following CsA treatment and also prevented CsA induced EMT. Using a wound-healing model, we observed that knockdown of miR-494 also prevented alterations in cell mobility and fibrosis associated with EMT.
Conclusions: Our study indicates that miR-494 plays a role in promoting CsA induced nephrotoxicity and EMT through its ability to target Pten. We suggest that manipulating miR-494 expression may represent a novel approach to preventing EMT associated with CsA induced nephrotoxicity.
To cite this abstract in AMA style:
Yuan J, Benway C, Bagley J, Iacomini J. microRNA-494 Promotes Cyclosporine-Induced Nephrotoxicity and Epithelial to Mesenchymal Transition By Inhibiting PTEN [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/microrna-494-promotes-cyclosporine-induced-nephrotoxicity-and-epithelial-to-mesenchymal-transition-by-inhibiting-pten/. Accessed May 17, 2025.« Back to 2015 American Transplant Congress