人脐带间充质干细胞通过IGF1R-CHK2-p53信号轴减轻2型糖尿病雄性大鼠糖尿病肾病

张昊; 王新舒; 胡铂; 李沛城; 伊尔番·阿不都艾尼; 赵红梅; 阿依娜·尔杰恩斯汗; 陈喜双; 王诗宇; 郭诺瑾; 袁健; 李昀辉; 李磊; 杨韫曈; 刘中民; 唐兆生; 王华

doi:10.1631/jzus.B2300182

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人脐带间充质干细胞通过IGF1R-CHK2-p53信号轴减轻2型糖尿病雄性大鼠糖尿病肾病

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Research Article | Updated：2024-07-17

人脐带间充质干细胞通过IGF1R-CHK2-p53信号轴减轻2型糖尿病雄性大鼠糖尿病肾病
Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2024年25卷第7期页码：568-580
Affiliations：

1.Department of Endocrinology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
2.Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
3.Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
4.Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, China
5.Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai East Hospital, Shanghai 200120, China
6.Ji’an Hospital, Shanghai East Hospital, Ji’an 343000, China
Funds：

the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai, the Discipline Leader Program of Pudong New District Health and Family Planning Commission(PWRd2018-02);the Natural Science Foundation of Jiangxi Province(20181ACB20021;20181BAB205044)
DOI：10.1631/jzus.B2300182
中图分类号：
CSTR：
纸质出版日期： 2024-07-15 ，

网络出版日期： 2024-07-10 ，

收稿日期： 2023-03-17 ，

修回日期： 2023-09-21 ，
Accepted：

张昊,王新舒,胡铂等.人脐带间充质干细胞通过IGF1R-CHK2-p53信号轴减轻2型糖尿病雄性大鼠糖尿病肾病[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(07):568-580.

Hao ZHANG, Xinshu WANG, Bo HU, et al. Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus[J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2024,25(7):568-580.
张昊,王新舒,胡铂等.人脐带间充质干细胞通过IGF1R-CHK2-p53信号轴减轻2型糖尿病雄性大鼠糖尿病肾病[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(07):568-580. DOI： 10.1631/jzus.B2300182.

Hao ZHANG, Xinshu WANG, Bo HU, et al. Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus[J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2024,25(7):568-580. DOI： 10.1631/jzus.B2300182.

摘要

糖尿病是一种以慢性高血糖为特征的疾病综合征，长期的高糖环境会导致活性氧（ROS）的产生和核DNA损伤。人脐带来源的间充质干细胞（HUcMSC）输注2型糖尿病（T2DM）大鼠后可诱导显著的抗糖尿病作用。胰岛素样生长因子1受体（IGF1R）在促进糖尿病患者的葡萄糖代谢中起着重要作用；然而，HUcMSC通过IGF1R和DNA损伤修复治疗糖尿病的机制尚不清楚。本研究经高脂饮食喂养和链脲佐菌素（STZ）给药诱导建立糖尿病大鼠模型，并给大鼠输注四次HUcMSC，随后检测血糖、白细胞介素-6（IL-6）、IL-10、肾小球基底膜和肾功能。通过共免疫沉淀测定与IGF1R相互作用的蛋白质；使用免疫组织化学（IHC）和蛋白质印迹分析检测IGF1R、磷酸检查点激酶2（p-CHK2）和p-p53的表达；采用酶联免疫吸附试验（ELISA）测定血清8-羟基脱氧鸟苷（8-OHdG）的水平；使用流式细胞术检测HUcMSC的表面标志物；采用油红O染色和茜素红染色鉴定HUcMSC的形态和表型。结果显示：糖尿病大鼠肾小球基底膜、血糖、IL-6/10水平和肾功能异常；胰岛素样生长因子1（IGF1）和IGF1R表达增加；IGF1R与CHK2相互作用；p-CHK2在IGF1R敲低细胞中的表达显著降低。当使用顺铂诱导DNA损伤时，p-CHK2的表达高于未经顺铂诱导的IGF1R敲低组。HUcMSC的输注改善了糖尿病大鼠的血糖异常，并保护了其肾脏结构和功能。糖尿病组IGF1、IGF1R、p-CHK2和p-p53的表达以及8-OHdG的水平与对照组相比显著增加，且在HUcMSC治疗后降低。综上所述，IGF1R可以与CHK2相互作用并介导DNA损伤，且HUcMSC对糖尿病大鼠肾损伤有保护作用。HUcMSC通过介导IGF1R-CHK2-p53信号通路是治疗糖尿病的潜在机制。

Abstract

Diabetes mellitus (DM) is a disease syndrome characterized by chronic hyperglycaemia. A long-term high-glucose environment leads to reactive oxygen species (ROS) production and nuclear DNA damage. Human umbilical cord mesenchymal stem cell (HUcMSC) infusion induces significant antidiabetic effects in type 2 diabetes mellitus (T2DM) rats. Insulin-like growth factor 1 (IGF1) receptor (IGF1R) is important in promoting glucose metabolism in diabetes; however

the mechanism by which HUcMSC can treat diabetes through IGF1R and DNA damage repair remains unclear. In this study

a DM rat model was induced with high-fat diet feeding and streptozotocin (STZ) administration and rats were infused four times with HUcMSC. Blood glucose

interleukin-6 (IL-6)

IL-10

glomerular basement membrane

and renal function were examined. Proteins that interacted with IGF1R were determined through coimmunoprecipitation assays. The expression of

IGF1R

phosphorylated checkpoint kinase 2 (p-CHK2)

and phosphorylated protein 53 (p-p53) was examined using immunohistochemistry (IHC) and western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of 8-hydroxydeoxyguanosine (8-OHdG). Flow cytometry experiments were used to detect the surface markers of HUcMSC. The identification of the morphology and phenotype of HUcMSC was performed by way of oil red “O” staining and Alizarin red staining. DM rats exhibited abnormal blood glucose and IL-6/10 levels and renal function changes in the glomerular basement membrane

increased the expression of IGF1 and IGF1R. IGF1R interacted with CHK2

and the expression of p-CHK2 was significantly decreased in

IGF1R

-knockdown cells. When cisplatin was used to induce DNA damage

the expression of p-CHK2 was higher than that in the

IGF1R

-knockdown group without cisplatin treatment. HUcMSC infusion ameliorated abnormalities and preserved kidney structure and function in DM rats. The expression of IGF1

IGF1R

p-CHK2

and p-p53

and the level of 8-OHdG in the DM group increased significantly compared with those in the control group

and decreased after HUcMSC treatment. Our results suggested that IGF1R could interact with CHK2 and mediate DNA damage. HUcMSC infusion protected against kidney injury in DM rats. The underlying mechanisms may include HUcMSC-mediated enhancement of diabetes treatment via the IGF1R-CHK2-p53 signalling pathway.

关键词

胰岛素样生长因子1受体（IGF1R）检查点激酶2（CHK2）p53糖尿病人脐带来源的间充质干细胞（HUcMSC）DNA损伤修复

Keywords

Insulin-like growth factor 1 receptor (IGF1R)Checkpoint kinase 2 (CHK2)Protein 53 (p53)Diabetes mellitusHuman umbilical cord mesenchymal stem cell (HUcMSC)DNA damage repair

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