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GDF15在肾移植缺血-再灌注损伤中的作用及机制研究

朱杰夫, 师朗, 宋志霞, 等. GDF15在肾移植缺血-再灌注损伤中的作用及机制研究[J]. 器官移植, 2022, 13(6): 749-756. doi: 10.3969/j.issn.1674-7445.2022.06.009
引用本文: 朱杰夫, 师朗, 宋志霞, 等. GDF15在肾移植缺血-再灌注损伤中的作用及机制研究[J]. 器官移植, 2022, 13(6): 749-756. doi: 10.3969/j.issn.1674-7445.2022.06.009
Zhu Jiefu, Shi Lang, Song Zhixia, et al. Role and mechanism of GDF15 in ischemia-reperfusion injury during kidney transplantation[J]. ORGAN TRANSPLANTATION, 2022, 13(6): 749-756. doi: 10.3969/j.issn.1674-7445.2022.06.009
Citation: Zhu Jiefu, Shi Lang, Song Zhixia, et al. Role and mechanism of GDF15 in ischemia-reperfusion injury during kidney transplantation[J]. ORGAN TRANSPLANTATION, 2022, 13(6): 749-756. doi: 10.3969/j.issn.1674-7445.2022.06.009

GDF15在肾移植缺血-再灌注损伤中的作用及机制研究

doi: 10.3969/j.issn.1674-7445.2022.06.009
基金项目: 

国家自然科学基金 82100803

湖北省自然科学基金 2021CFB101

详细信息
    作者简介:
    通讯作者:

    吴雄飞,Email: wuxfei@126.com

  • 中图分类号: R617, R692

Role and mechanism of GDF15 in ischemia-reperfusion injury during kidney transplantation

More Information
  • 摘要:   目的  探讨生长与分化因子(GDF)15在肾移植缺血-再灌注损伤(IRI)中的作用及机制。  方法  选取野生型供体小鼠9只,野生型受体小鼠9只,分别于术后4、24、72 h取3只受体小鼠的移植肾,进行GDF家族转录组学分析,检测各组肾组织GDF15的表达情况。选取野生型供体小鼠5只,GDF15敲除型供体小鼠5只,野生型受体小鼠10只,根据实验方案将小鼠分为野生型假手术组、野生型移植组、GDF15敲除假手术组、GDF15敲除移植组,于术后72 h提取血清及肾组织样本,对比各组肾功能、肾小管损伤情况、炎症细胞浸润、炎症因子及Toll样受体4(TLR4)、核因子(NF)-κB表达水平。选取野生型供体小鼠9只,GDF15敲除型供体小鼠9只,野生型受体小鼠18只,根据实验方案将小鼠分为野生型移植组、GDF15敲除移植组,观察肾移植术后两组生存率。  结果  GDF15是移植肾转录组学中上调最多的GDF家族基因,主要在肾小管中表达。与假手术组比较,移植组小鼠肾功能下降;与野生型移植组比较,GDF15敲除移植组小鼠血清肌酐、血尿素氮水平升高(均为P < 0.05)。野生型移植组小鼠术后1周生存率为87.6%,GDF15敲除移植组小鼠术后1周生存率为41.8%。GDF15敲除移植组肾损伤分子(KIM)-1表达增多,肾小管损伤评分更高。野生型移植组肾小管可见溶解或坏死,髓外和皮质中可见管型形成,而GDF15敲除移植组肾小管坏死及管型更加明显。移植组髓过氧化物酶(MPO)和F4/80表达增多,且GDF15敲除移植组炎症细胞浸润加重。与假手术组比较,移植组肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β和IL-6表达水平升高;与野生型移植组比较,GDF15敲除移植组TNF-α、IL-1β和IL-6表达水平升高(均为P < 0.05)。移植组肾组织中TLR4、NF-κB表达较假手术组增多;GDF15敲除移植组肾组织中TLR4和NF-κB表达较野生型移植组增多。  结论  GDF15可减轻移植肾IRI,其作用机制可能与抑制TLR4-NF-κB信号通路有关。

     

  • 图  1  模型建立方法与实验方案

    注:A图为GDF15敲除方案;B图为GDF15敲除后蛋白质印迹法检测结果;C图为动物实验方案。

    Figure  1.  Model building method and experimental scheme

    图  2  GDF家族转录组学

    注:FPKM为每千个碱基的转录每百万映射读取的片段(fragments per kilobase of exon model per million mapped fragments);与假手术组比较,aP < 0.05。

    Figure  2.  Transcriptome of GDF family

    图  3  各组小鼠肾组织GDF15蛋白的表达情况及病理学结果

    注:A图为GDF15蛋白质印迹法检测结果;B图为各组GDF15免疫组化染色结果(×400);C图为各组HE染色结果(×400)。

    Figure  3.  Expression of GDF15 protein and histopathological results of renal tissue in mice of each group

    图  4  各组小鼠术后肾功能及生存率

    注:A图为各组小鼠血清肌酐水平;B图为各组小鼠血尿素氮水平;C图为两组鼠移植后的生存曲线;与假手术组比较,aP < 0.05;与野生型移植组比较,bP < 0.05。

    Figure  4.  Renal function and survival rate of mice in each group after operation

    图  5  各组小鼠肾小管损伤情况及肾小管损伤评分

    注:A图为各组小鼠肾组织KIM-1表达情况(免疫组化,× 400);B图为各组小鼠肾组织HE染色结果(× 400);C图为各组小鼠肾小管损伤评分;与假手术组比较,aP < 0.05,与野生型移植组比较,bP < 0.05。

    Figure  5.  Renal tubular injury and renal tubule injury score of mice in each group

    图  6  各组肾组织炎症细胞浸润及炎症因子表达情况

    注:A图为MPO免疫组化染色结果(× 400);B图为F4/80免疫组化染色结果(× 400);C图为各组炎症因子水平;与假手术组比较,aP < 0.05;与野生型移植组比较,bP < 0.05。

    Figure  6.  Inflammatory cell infiltration and expression of inflammatory factors in renal tissues of each group

    图  7  各组肾组织TLR4、NF-κB表达情况(免疫荧光,× 400)

    Figure  7.  Expression of TLR4 and NF-κB in renal tissues of each group

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出版历程
  • 收稿日期:  2022-08-31
  • 网络出版日期:  2022-11-14
  • 刊出日期:  2022-11-15

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