Renal inhibition of miR-181a ameliorates 5-fluorouracil-induced mesangial cell apoptosis and nephrotoxicity.
Renal inhibition of miR-181a ameliorates 5-fluorouracil-induced mesangial cell apoptosis and nephrotoxicity.
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miR-181a 的肾抑制可改善 5-氟尿嘧啶诱导的系膜细胞凋亡和肾毒性
DOI：
10.1038/s41419-018-0677-8
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发表时间：
2018-05-23
影响因子：
9
通讯作者：
Liang SJ
中科院分区：
文献类型：
--
作者：
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
肾毒性的发展在很大程度上限制了化疗的临床应用。miRNAs能够靶向多种基因并参与多种细胞过程的调节，包括细胞凋亡和死亡。我们的研究表明，5-氟尿嘧啶（5-FU）处理后，肾系膜细胞和肾组织中miR-181 a的表达显著增加，这与杆状病毒抑制凋亡蛋白重复序列6（BIRC 6）表达减少和凋亡率增加有关。miR-181 a的表达增强了5-FU诱导的p53依赖性线粒体凋亡，包括Bcl-2/Bax比值下降、线粒体膜电位丧失、细胞色素c释放以及caspase-9和caspase-3激活。然而，miR-181 a的抑制与5-FU诱导的p53介导的线粒体凋亡减少相关。此外，miR-181 a通过减少泛素介导的蛋白降解增加BIRC 6下游基因p53蛋白表达和转录活性。我们发现miR-181 a直接靶向BIRC 6 mRNA的3′-UTR，并负调控BIRC 6的表达。在体内研究中，用携带miR-181 a-tough decoy的腺相关病毒敲低miR-181 a可减弱5-FU诱导的肾细胞凋亡、炎症和肾损伤。总之，这些结果表明，miR-181 a通过靶向BIRC 6增加p53蛋白表达和转录活性，并促进5-FU诱导的系膜细胞凋亡。抑制miR-181 a可改善5-FU诱导的肾毒性，这表明miR-181 a可能是化疗期间肾毒性治疗的新治疗靶点。
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.
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影响因子：
16
作者：
Bartke, T;Pohl, C;Jentsch, S
通讯作者：
Jentsch, S
影响因子：
5.7
作者：
Bhatt, Kirti;Zhou, Li;Dong, Zheng
通讯作者：
Dong, Zheng
影响因子：
2.8
作者：
Al-Asmari, A. K.;Al-Zahrani, A. M.;Al Amri, M. Ali
通讯作者：
Al Amri, M. Ali
影响因子：
--
作者：
Crippa E;Folini M;Pennati M;Zaffaroni N;Pierotti MA;Gariboldi M
通讯作者：
Gariboldi M
影响因子：
4.4
作者：
Ouyang, Yi-Bing;Lu, Yu;Yue, Sibiao;Giffard, Rona G.
通讯作者：
Giffard, Rona G.