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Renal inhibition of miR-181a ameliorates 5-fluorouracil-induced mesangial cell apoptosis and nephrotoxicity
- Source :
- Cell Death and Disease, Vol 9, Iss 6, Pp 1-14 (2018), Cell Death & Disease
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group, 2018.
-
Abstract
- The development of nephrotoxicity largely limits the clinical use of chemotherapy. MiRNAs are able to target various genes and involved in the regulation of diverse cellular processes, including cell apoptosis and death. Our study showed that miR-181a expression was significantly increased after 5-fluorouracil (5-FU) treatment in renal mesangial cells and kidney tissue, which was associated with decreased baculoviral inhibition of apoptosis protein repeat-containing 6 (BIRC6) expression and increased apoptotic rate. Enforced miR-181a expression enhanced 5-FU-induced p53-dependent mitochondrial apoptosis, including declined Bcl-2/Bax ratio, loss of mitochondrial membrane potential, cytochrome c release, and caspase-9 and caspase-3 activation. However, inhibition of miR-181a was associated with reduced p53-mediated mitochondrial apoptosis induced by 5-FU. Moreover, miR-181a increased BIRC6 downstream gene p53 protein expression and transcriptional activity by reducing ubiquitin-mediated protein degradation. We found that miR-181a directly targeted 3′-UTR of BIRC6 mRNA and negatively regulated BIRC6 expression. In vivo study, knockdown of miR-181a with adeno-associated virus harboring miR-181a-tough decoy attenuated 5-FU-induced renal cell apoptosis, inflammation and kidney injury. In conclusion, these results demonstrate that miR-181a increases p53 protein expression and transcriptional activity by targeting BIRC6 and promotes 5-FU-induced apoptosis in mesangial cells. Inhibition of miR-181a ameliorates 5-FU-induced nephrotoxicity, suggesting that miR-181a may be a novel therapeutic target for nephrotoxicity treatment during chemotherapy.
- Subjects :
- 0301 basic medicine
Cancer Research
Transcription, Genetic
Immunology
Apoptosis
Protein degradation
Kidney
Article
Inhibitor of Apoptosis Proteins
Nephrotoxicity
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
microRNA
medicine
Animals
Humans
lcsh:QH573-671
Inflammation
Gene knockdown
Base Sequence
Mesangial cell
Chemistry
lcsh:Cytology
Cell Biology
HCT116 Cells
Mitochondria
Mice, Inbred C57BL
MicroRNAs
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Mesangial Cells
Cancer research
Kidney Diseases
Fluorouracil
Tumor Suppressor Protein p53
Signal transduction
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 9
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Cell Death and Disease
- Accession number :
- edsair.doi.dedup.....422e20e71209f9165eff690f430a852c