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2017年第11期
miR-146a在小鼠肾脏缺血再灌注损伤中的表达及作用
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DOI:
作者:
戴艳
DAI yan, LI qing,JIA ping, FANG Yi, LIU Hong , DING xiaoqing*
作者单位:
复旦大学附属中山医院
Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China;
关键词:
miR-146a;缺血再灌注;TNF受体相关因子6;IL-1受体相关激酶1
miR-146a; ischemia-reperfusion; TRAF6; IRAK-1
摘要:
目的 探讨miR-146a在小鼠肾脏缺血再灌注(I/R)损伤中的表达和具体作用机制。方法 雄性8-10周C57BL/6小鼠,随机分为假手术组(anti-scrambled +Sham);anti-miR-146a干预组(anti-miR-146a+I/R):尾静脉注射锁核苷酸(locked nucleic acid, LNA)修饰的anti-miR-146a,继之予I/R手术,恢复灌注后继之分别于6h、24h、48h后处死小鼠;anti-scramble干预组(anti-scrambled +I/R):尾静脉注射anti-scramble,继之予I/R手术,每组每个观察点n=6;对于I/R时间性观察再增加3d、5d、7d和14d时间点,每组每个观察点n=4。结果 与Sham组相比较,缺血再灌注肾损伤可以呈时间依耐性上调肾组织miR-146a的表达,7d到达高峰;抑制miR-146a的表达较scrambled组观察6-48h并没有明显增加小鼠缺血再灌注血清肌酐(24h, Scr, 183.2 ± 9.1 umol/l vs.156.8± 13.3umol/l (n=5, p>0.05)和小管间质损伤及其靶基因(TRAF6和IRAK-1)合成和肾脏细胞凋亡(59.80 ±2.6/HPF and 50.50 ± 3.7/HPF vs.1.50 ± 0.6/HPF,p<0.001)和炎症因子表达。结论 I/R可以上调miR-146a表达,但再灌注早期(6-48h)抑制miR-146a并不能进一步加重肾脏缺血再灌注损伤。
[Abstract] Objective With highly effective in a mouse model of renal I/R injury knockdown of miR-146a, we were able to discern the role of miR-146a underlying I/R injury. Methods Male C57BL/6 mice weighing 22-25g were used in this study, and randomly divided into different groups as following: anti-scrambled+Shamgroup, mice only received isolation of renal bilateral pedicles, without clamping pedicles. I/R group, 30 min ischemia was induced by clamping bilateral pedicles followed by reperfusion; anti-miR-146a+I/R group and anti-scramble +I/R group, LNA-modified anti-scrambled or anti-miR-146a oligonucleotides (10mg/kg) were administered to mice through the tail vein and after 24h renal I/R was performed (n=6 in each group). Blood samples and kidneys were collected at 6, 24, and 48h after renal reperfusion and additional 3,5,7,14 days, groups samples were prepared for I/R time course experiments. Results miR-146a was up-regulated following I/R injury compared to sham samples at day 3 and achieved its peak at day7. miR-146a level in I/R+anti-miR-146a group was markedly decreased(p<0.001) whereas there was no significant elevation in anti-scrambled +I/R group at 6-48 h after IRI related to sham-operated controls (p>0.05). Time-course assay showed that knockdown of miR-146a didn’t alter the level of Scr 24h after IRI in anti-miR-146a+I/R group when compared with anti-scramble +I/R group (24h,Scr, 183.2 ± 9.1umol/l vs. 156.8± 13.3umol/l; n=5, p>0.05 ) and did not exacerbate renal function and histologic damage. knockdown of miR-146a from mice in anti-miR-146a+I/R group did not induce significant upregulation of TRAF6 and IRAK-1,two target effectors of miR-146a both in mRNA and protein levels. Both mice from anti-miR-146a+I/R and anti-scrambled +I/R group showed a substantial increase of apoptotic cells in kidneys 24h after renal IRI when compared with sham operated mice (59.80 ±2.6/HPF and 50.50 ± 3.7/HPF vs.1.50 ± 0.6/HPF,p<0.001).Mice receiving scrambled anti-miR-146a following IRI procedures did not alter kidney mRNA levels of inflammatory cytokine production(MCP-1,TNF-α 、IL-1β 、IL-6、IL-10)compared with mice receiving anti-Scramble(p>0.05),although there was a significant increase in both above groups related to sham-operated control mice(p<0.05). Conclusions I/R injury upregulated miR-146a and its target effector TRAF6, IRAK-1 in time dependent manner and in protein level but not in mRNA level. A LNA-modified anti-miR-146a given before I/R procedures knocked down miR-146a effectively but did not exacerbate subsequent renal IRI through 6h and 48h functionally and morphologically; Knockdown of miR-146a did not induce significant upregulation of TRAF6 and IRAK-1 expression, eventually leading to increasing of tubular cell apoptosis. Knockdown of miR-146a in vivo doesn't aggravate the kidney damage at early stage(6-48h) of renal I/R injury.
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