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Renal inhibition of miR-181a ameliorates 5-fluorouracil-induced mesangial cell
apoptosis and nephrotoxicity
#MMPMID29795190
Liu XY
; Zhang FR
; Shang JY
; Liu YY
; Lv XF
; Yuan JN
; Zhang TT
; Li K
; Lin XC
; Liu X
; Lei Q
; Fu XD
; Zhou JG
; Liang SJ
Cell Death Dis
2018[May]; 9
(6
): 610
PMID29795190
show ga
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.
|*Apoptosis/drug effects/genetics
[MESH]
|Animals
[MESH]
|Base Sequence
[MESH]
|Fluorouracil/*adverse effects
[MESH]
|HCT116 Cells
[MESH]
|Humans
[MESH]
|Inflammation/pathology
[MESH]
|Inhibitor of Apoptosis Proteins/metabolism
[MESH]
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