褪黑素对脓毒症小鼠急性肾损伤及miR-146a水平的影响

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摘要目的探讨褪黑素（MT）对内毒素（LPS）诱导的脓毒症肾损伤小鼠炎症及肾脏细胞凋亡的影响，以及MT对脓毒症肾损伤的作用及其与microRNA-146a（miR-146a）的关系。方法将48只雄性Balb/c小鼠按照随机数字表法分为假手术组（Sham组）、MT治疗组（MT组）以及假治疗组（NS组），每组16只。MT组、NS组小鼠腹腔注射LPS（10 mg/kg体重）制备脓毒症模型，MT组小鼠于建模前半小时、建模时、伤后4 h分3次注射MT（30 mg/kg体重），NS组及Sham组小鼠在MT组相应给药时间点注射等量生理盐水。LPS处理24 h后，检测各组白细胞介素（IL）-1β、IL-6 mRNA的水平、miR-146a的水平、凋亡蛋白Caspase-3、Bax的表达情况，以及血清肌酐（Cr）及尿素氮（BUN）水平。LPS处理72 h后观察各组小鼠肾脏病理变化及损伤情况。结果 ①Sham组肾小球、肾小管结构完整，NS组肾小管内管型形成，肾小管结构不清，肾小球固缩，大量炎症细胞浸润；MT组坏死肾小球数目明显少于NS组。②NS组、MT组血清Cr、BUN含量显著高于Sham组（P ＜ 0.01），MT组血清Cr、BUN含量则显著低于NS组（P ＜ 0.01）。③MT组肾脏组织Cleaved-caspase-3、Bax表达量显著低于NS组（P ＜ 0.01）。④三组肾脏组织中IL-1β和IL-6水平比较，差异有统计学意义（P ＜ 0.05），其中MT组肾脏组织IL-1β、IL-6显著低于NS组（P ＜ 0.01）。⑤三组肾脏组织中miR-146a水平比较，差异有高度统计学意义（P ＜ 0.01），MT组显著高于NS组（P ＜ 0.01）。结论 MT对LPS诱导的脓毒症小鼠肾损伤有明显治疗作用，这种治疗作用可能是通过上调miR-146a，进而抑制炎症及细胞凋亡实现的。

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	张家宁1 曹梦远2 李林成1 刘铭传1 刘洋3 何亭3▲

关键词 ：褪黑素, 脓毒症, 肾损伤, 微小RNA-146a

Abstract：Objective To investigate the effect of melatonin (MT) on apoptosis of renal cells and inflammation in lipopolysaccharide (LPS)-induced septic mice, and to explore the effect of MT on renal injury in sepsis as well as the role that microRNA-146a(miR-146a) plays. Methods Forty-eight male Balb/c mice were divided into sham-operated group (Sham group), MT treatment group (MT group) and placebo group (NS group) according to random number table method, with 16 mice in each group. Mice in the latter two groups were injected with LPS (10 mg/kg body weight) intraperitoneally to prepare sepsis model. Mice in MT group were injected with MT (30 mg/kg body weight) three times separately at half an hour before LPS injection, the same time as LPS injection and 4 hours after injection. At the same time，mice in NS group and Sham group were injected with same volume saline. After LPS treatment for 24 hours, the levels of interleukin (IL)-1β and IL-6 mRNA, miR-146a, the expression of apoptotic proteins Caspase-3 and Bax, serum creatinine (Cr) and urea nitrogen (BUN) were detected. After LPS treatment for 72 hours, the renal pathological changes and injuries of mice in each group were observed. Results ①The renal structure was normal in Sham group. The renal tubules in NS group were of tubular type, with unclear tubular structure, glomerular pyknosis, and a large number of inflammatory cells infiltrating; the number of necrotic glomeruli in MT group was much less than that in NS group. ②The levels of serum Cr and BUN in NS group were significantly higher than those in Sham group (P ＜ 0.01). The levels of Cr and BUN in MT group mice were significantly lower than those in NS group (P ＜ 0.01). ③The levels of Cleaved-caspase 3 and Bax in MT group mice were significantly lower than those in NS group (P ＜ 0.01). ④The levels of IL-1β and IL-6 in these three groups mice had statistically significant difference (P ＜ 0.05). In MT group, the levels of IL-1β and IL-6 in renal tissues were lower than those in NS group (P ＜ 0.01). ⑤The levels of miR-146a in renal tissues were highly statistically different in these three groups mice (P ＜ 0.01). In MT group, it was significantly higher than that in NS group (P ＜ 0.01). Conclusion MT can significantly improve renal injury in LPS-induced septic mice, which may related to the upregulation of miR-146a and suppression of inflammation and cell apoptosis.

Key words： Melatonin Sepsis Renal injury microRNA-146a

基金资助:国家自然科学基金青年科学基金项目（816016 89、81501666）；
空军军医大学西京医院学科助推计划基础研究探索项目（XJZT15M11）。

通讯作者: ▲通讯作者

引用本文:

张家宁1 曹梦远2 李林成1 刘铭传1 刘洋3 何亭3▲. 褪黑素对脓毒症小鼠急性肾损伤及miR-146a水平的影响[J]. 中国医药导报, 2019, 16(5): 4-8.
ZHANG Jianing1 CAO Mengyuan2 LI Lincheng1 LIU Mingchuan1 LIU Yang3 HE Ting3▲. Effect of melatonin on acute kidney injury and miR-146a level in septic mice. 中国医药导报, 2019, 16(5): 4-8.

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