妊娠糖尿病抑制胎盘AKT-mTOR及SIRT1信号通路

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目的:探讨AKT-mTOR信号通路与SIRT1在妊娠期糖尿病(gestational diabetes mellitus,GDM)编程胎儿生长发育中的作用。方法:收集重庆医科大学附属第一医院2014年12月至2015年6月分娩的15例GDM和15例正常产妇的胎盘组织,应用Western blot检测胎盘中AKT-mTOR磷酸化水平与SIRT1的表达水平。以人绒毛外滋养细胞(HTR8/SVneo)体外培养,分为空白对照组、渗透对照组和高糖组。各组处理后使用Western blot检测AKT-mTOR总蛋白和磷酸化水平,以及SIRT1的表达水平,应用流式细胞术(flow cytometry)检测各组的凋亡率。db/+杂合雌鼠妊娠至18.5 d处死后,取其胎盘组织,对其进行基因型鉴定后,选取野生型子代胎盘为GDM组,C57雌鼠胎盘组织为正常对照组,每组各6只。然后应用Western blot检测胎盘组织中AKT-mTOR信号通路。结果:AKT及其下游mTOR磷酸化水平在GDM胎盘中的表达明显低于正常胎盘(0.347±0.031 vs.1.000±0.175,P=0.004;0.465±0.045 vs.1.000±0.098,P=0.000)。同样,GDM组的SIRT1的表达水平也明显低于正常组(0.682±0.055 vs.1.000±0.127,P=0.044);在细胞模型中,经高糖处理后,AKT-mTOR磷酸化水平明显降低(0.512±0.056 vs.1.103±0.111,P=0.023;0.262±0.091 vs.1.153±0.057,P=0.001),而SIRT1的表达同样明显降低(0.472±0.034 vs.1.013±0.098,P=0.040)。高糖组的细胞凋亡率明显升高(14.550±1.624 vs.9.547±0.685,P=0.032)。在动物模型中,GDM组的AKT-mTOR磷酸化水平明显降低(0.527±0.080 vs 1.000±0.055,P=0.003;0.418±0.059 vs.1.000±0.084,P=0.001)。结论:宫内高血糖环境可能通过抑制胎盘AKT-mTOR信号通路,从而编程子代的发育轨迹。 Objective: To investigate the role of AKT-mTOR signaling pathway and SIRT1 in the fetal development of gestational diabetes mellitus (GDM). Methods: The placental tissues of 15 GDM and 15 normal pregnant women delivered from the First Affiliated Hospital of Chongqing Medical University from December 2014 to June 2015 were collected. The level of AKT-mTOR phosphorylation and the expression of SIRT1 in the placenta were detected by Western blot . Human trophoblast cells (HTR8 / SVneo) were cultured in vitro and divided into blank control group, infiltration control group and high glucose group. After treatment, the total protein and phosphorylation of AKT-mTOR and the expression of SIRT1 were detected by Western blot. The apoptosis rate of each group was detected by flow cytometry. db / + heterozygous female rats were sacrificed after 18.5 d of gestation, and their placenta tissues were taken for genotypic identification. Then, the wild-type offspring placenta were selected as GDM group and the placenta of C57 female rats as normal control group. 6 only. Western blot was used to detect the AKT-mTOR signaling pathway in placenta. Results: The phosphorylation level of AKT and its downstream mTOR in GDM placenta was significantly lower than that in normal placenta (0.347 ± 0.031 vs.1.000 ± 0.175, P = 0.004; 0.465 ± 0.045 vs.1.000 ± 0.098, P = 0.000). Similarly, the level of SIRT1 expression in GDM group was significantly lower than that in the normal group (0.682 ± 0.055 vs.1.000 ± 0.127, P = 0.044). In the cellular model, phosphorylation of AKT-mTOR was significantly decreased 0.512 ± 0.056 vs.1.103 ± 0.111, P = 0.023; 0.262 ± 0.091 vs.1.153 ± 0.057, P = 0.001). However, the expression of SIRT1 was also significantly decreased (0.472 ± 0.034 vs.1.013 ± 0.098, P = 0.040). The apoptosis rate in high glucose group was significantly higher (14.550 ± 1.624 vs.9.547 ± 0.685, P = 0.032). In animal models, phosphorylation of AKT-mTOR was significantly decreased in GDM group (0.527 ± 0.080 vs 1.000 ± 0.055, P = 0.003; 0.418 ± 0.059 vs.1.000 ± 0.084, P = 0.001). CONCLUSION: Intrauterine hyperglycemia may be programmed to track the development of offspring by inhibiting the AKT-mTOR signaling pathway in the placenta.
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