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MicroRNA-494 promotes cyclosporine-induced nephrotoxicity and epithelial to mesenchymal transition by inhibiting PTEN

J Yuan1, C J Benway1,2, J Bagley1

  • 1Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA.

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
|April 10, 2015
PubMed

Insights

MicroRNA-494 (miR-494) promotes cyclosporine-induced nephrotoxicity by targeting PTEN, leading to kidney cell damage. Modulating miR-494 may offer a new strategy to prevent this complication.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclosporine (CsA) is a vital immunosuppressant with nephrotoxicity as a significant clinical challenge.
  • The underlying mechanisms of CsA-induced kidney damage, particularly the role of microRNAs, require further elucidation.

Purpose of the Study:

  • To investigate the involvement of microRNAs in cyclosporine-induced nephrotoxicity.
  • To determine the specific role of microRNA mmu-miR-494 (miR-494) in this process.

Main Methods:

  • Administered CsA to mice to induce nephrotoxicity and analyzed microRNA expression.
  • Utilized in vitro models of tubular epithelial cells exposed to CsA to study epithelial-mesenchymal transition (EMT).
  • Performed molecular analyses to identify miR-494 targets and assess its regulatory function on PTEN.

Main Results:

  • CsA treatment in mice led to increased expression of miR-494 and nephrotoxicity.
  • In vitro, CsA-induced EMT in tubular cells was associated with miR-494 upregulation and PTEN downregulation.
  • miR-494 was confirmed to directly target and downregulate PTEN; blocking this interaction prevented CsA-induced EMT.

Conclusions:

  • miR-494 plays a critical role in promoting CsA-induced nephrotoxicity by targeting PTEN and driving EMT.
  • Targeting miR-494 presents a potential therapeutic avenue for mitigating CsA-associated kidney damage and EMT.
Keywords:
basic (laboratory) research/sciencecalcineurin inhibitor: cyclosporine A (CsA)complicationdrug toxicityimmunosuppressantimmunosuppression/immune modulationkidney failure/injurykidney transplantation/nephrologymolecular biology: micro RNAtranslational research/science

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