Full Text:   <366>

Summary:  <18>

Suppl. Mater.: 

CLC number: 

On-line Access: 2024-07-17

Received: 2023-03-17

Revision Accepted: 2023-09-21

Crosschecked: 2024-07-17

Cited: 0

Clicked: 505

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Zhaosheng TANG

0000-0002-2398-4853

Hua WANG

0000-0001-9592-414X

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2024 Vol.25 No.7 P.568-580

http://doi.org/10.1631/jzus.B2300182


Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus


Author(s):  Hao ZHANG, Xinshu WANG, Bo HU, Peicheng LI, Yierfan ABUDUAINI, Hongmei ZHAO, Ayinaer JIEENSIHAN, Xishuang CHEN, Shiyu WANG, Nuojin GUO, Jian YUAN, Yunhui LI, Lei LI, Yuntong YANG, Zhongmin LIU, Zhaosheng TANG, Hua WANG

Affiliation(s):  Department of Endocrinology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China; more

Corresponding email(s):   tjwh02@163.com, zhaoshengtang@aliyun.com

Key Words:  Insulin-like growth factor 1 receptor (IGF1R), Checkpoint kinase 2 (CHK2), Protein 53 (p53), Diabetes mellitus, Human umbilical cord mesenchymal stem cell (HUcMSC), DNA damage repair


Hao ZHANG, Xinshu WANG, Bo HU, Peicheng LI, Yierfan ABUDUAINI, Hongmei ZHAO, Ayinaer JIEENSIHAN, Xishuang CHEN, Shiyu WANG, Nuojin GUO, Jian YUAN, Yunhui LI, Lei LI, Yuntong YANG, Zhongmin LIU, Zhaosheng TANG, Hua WANG. 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, 2024, 25(7): 568-580.

@article{title="Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus",
author="Hao ZHANG, Xinshu WANG, Bo HU, Peicheng LI, Yierfan ABUDUAINI, Hongmei ZHAO, Ayinaer JIEENSIHAN, Xishuang CHEN, Shiyu WANG, Nuojin GUO, Jian YUAN, Yunhui LI, Lei LI, Yuntong YANG, Zhongmin LIU, Zhaosheng TANG, Hua WANG",
journal="Journal of Zhejiang University Science B",
volume="25",
number="7",
pages="568-580",
year="2024",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2300182"
}

%0 Journal Article
%T Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus
%A Hao ZHANG
%A Xinshu WANG
%A Bo HU
%A Peicheng LI
%A Yierfan ABUDUAINI
%A Hongmei ZHAO
%A Ayinaer JIEENSIHAN
%A Xishuang CHEN
%A Shiyu WANG
%A Nuojin GUO
%A Jian YUAN
%A Yunhui LI
%A Lei LI
%A Yuntong YANG
%A Zhongmin LIU
%A Zhaosheng TANG
%A Hua WANG
%J Journal of Zhejiang University SCIENCE B
%V 25
%N 7
%P 568-580
%@ 1673-1581
%D 2024
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2300182

TY - JOUR
T1 - Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus
A1 - Hao ZHANG
A1 - Xinshu WANG
A1 - Bo HU
A1 - Peicheng LI
A1 - Yierfan ABUDUAINI
A1 - Hongmei ZHAO
A1 - Ayinaer JIEENSIHAN
A1 - Xishuang CHEN
A1 - Shiyu WANG
A1 - Nuojin GUO
A1 - Jian YUAN
A1 - Yunhui LI
A1 - Lei LI
A1 - Yuntong YANG
A1 - Zhongmin LIU
A1 - Zhaosheng TANG
A1 - Hua WANG
J0 - Journal of Zhejiang University Science B
VL - 25
IS - 7
SP - 568
EP - 580
%@ 1673-1581
Y1 - 2024
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2300182


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.

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1,王新舒2,4,6,胡铂3,李沛城1,伊尔番·阿不都艾尼1,赵红梅1,阿依娜·尔杰恩斯汗1,陈喜双1,王诗宇1,郭诺瑾1,袁健2,4,6,李昀辉2,6,李磊2,杨韫曈4,刘中民3,5,唐兆生1,王华1,5
1上海市东方医院(同济大学附属东方医院)内分泌科,中国上海市,200120
2上海市东方医院(同济大学附属东方医院)转化医学研究中心,中国上海市,200120
3上海市东方医院(同济大学附属东方医院)心内科,中国上海市,200120
4同济大学医学院 生物化学与分子生物学系,中国上海市,200331
5上海市东方医院上海干细胞研究与临床转化研究所,中国上海市,200120
6上海市东方医院吉安医院,中国吉安市,343000
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。

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

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AdaikalakoteswariA, RemaM, MohanV, et al., 2007. Oxidative DNA damage and augmentation of poly(ADP-ribose) polymerase/nuclear factor-kappa B signaling in patients with Type 2 diabetes and microangiopathy. Int J Biochem Cell Biol, 39(9):1673-1684.

[2]Ansarullah, JainC, FarFF, et al., 2021. Inceptor counteracts insulin signalling in β-cells to control glycaemia. Nature, 590(7845):326-331.

[3]ArmataHL, GolebiowskiD, JungDY, et al., 2010. Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis. Mol Cell Biol, 30(24):5787-5794.

[4]BernardoME, FibbeWE, 2013. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell, 13(4):392-402.

[5]BrunerSD, NormanDP, VerdineGL, 2000. Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature, 403(6772):859-866.

[6]CerielloA, 2003. New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care, 26(5):1589-1596.

[7]ChitnisMM, YuenJSP, ProtheroeAS, et al., 2008. The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res, 14(20):6364-6370.

[8]ChoJ, D'AntuonoM, GlicksmanM, et al., 2018. A review of clinical trials: mesenchymal stem cell transplant therapy in type 1 and type 2 diabetes mellitus. Am J Stem Cells, 7(4):82-93.

[9]Cingel-RisticV, SchrijversBF, van VlietAK, et al., 2005. Kidney growth in normal and diabetic mice is not affected by human insulin-like growth factor binding protein-1 administration. Exp Biol Med, 230(2):135-143.

[10]CollinsAR, RašlováK, SomorovskáM, et al., 1998. DNA damage in diabetes: correlation with a clinical marker. Free Radic Biol Med, 25(3):373-377.

[11]DingDC, ChangYH, ShyuWC, et al., 2015. Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy. Cell Transplant, 24(3):339-347.

[12]DuXL, MatsumuraT, EdelsteinD, et al., 2003. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest, 112(7):1049-1057.

[13]FlyvbjergA, BornfeldtKE, MarshallSM, et al., 1990. Kidney IGF-I mRNA in initial renal hypertrophy in experimental diabetes in rats. Diabetologia, 33(6):334-338.

[14]GuariguataL, WhitingDR, HambletonI, et al., 2014. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract, 103(2):137-149.

[15]GurevichE, SegevY, LandauD, 2021. Growth hormone and IGF1 actions in kidney development and function. Cells, 10(12):3371.

[16]HodgkinsonAD, BartlettT, OatesPJ, et al., 2003. The response of antioxidant genes to hyperglycemia is abnormal in patients with type 1 diabetes and diabetic nephropathy. Diabetes, 52(3):846-851.

[17]JiaHY, YanYM, LiangZF, et al., 2018. Autophagy: a new treatment strategy for MSC-based therapy in acute kidney injury (Review). Mol Med Rep, 17(3):3439-3447.

[18]KongYL, ShenY, NiJ, et al., 2016. Insulin deficiency induces rat renal mesangial cell dysfunction via activation of IGF-1/IGF-1R pathway. Acta Pharmacol Sin, 37(2):217-227.

[19]LahigueraÁ, HyroššováP, FiguerasA, et al., 2020. Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors. EMBO Mol Med, 12(6):e11217.

[20]LandauD, SegevY, AfarganM, et al., 2001. A novel somatostatin analogue prevents early renal complications in the nonobese diabetic mouse. Kidney Int, 60(2):505-512.

[21]LandauD, EshetR, TroibA, et al., 2009. Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation. Endocrine, 36(1):126-134.

[22]LeeSH, 2018. The advantages and limitations of mesenchymal stem cells in clinical application for treating human diseases. Osteoporos Sarcopenia, 4(4):150.

[23]LeinonenJ, LehtimäkiT, ToyokuniS, et al., 1997. New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus. FEBS Lett, 417(1):150-152.

[24]LiJY, DongR, YuJL, et al., 2018. Inhibitor of IGF1 receptor alleviates the inflammation process in the diabetic kidney mouse model without activating SOCS2. Drug Des Devel Ther, 12:2887-2896.

[25]LoeschMM, CollierAE, SouthernDH, et al., 2016. Insulin-like growth factor-1 receptor regulates repair of ultraviolet B-induced DNA damage in human keratinocytes in vivo. Mol Oncol, 10(8):1245-1254.

[26]MaciasMI, GrandeJ, MorenoA, et al., 2010. Isolation and characterization of true mesenchymal stem cells derived from human term decidua capable of multilineage differentiation into all 3 embryonic layers. Am J Obstet Gynecol, 203(5):495.e9-495.e23.

[27]MeyerS, ChiblyAM, BurdR, et al., 2017. Insulin-like growth factor-1-mediated DNA repair in irradiated salivary glands is sirtuin-1 dependent. J Dent Res, 96(2):225-232.

[28]NieP, BaiX, LouY, et al., 2021. Human umbilical cord mesenchymal stem cells reduce oxidative damage and apoptosis in diabetic nephropathy by activating Nrf2. Stem Cell Res Ther, 12:450.

[29]NishikawaT, EdelsteinD, DuXL, et al., 2000. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature, 404(6779):787-790.

[30]PallerMS, NeumannTV, 1991. Reactive oxygen species and rat renal epithelial cells during hypoxia and reoxygenation. Kidney Int, 40(6):1041-10499.

[31]PapaharalambusCA, GriendlingKK, 2007. Basic mechanisms of oxidative stress and reactive oxygen species in cardiovascular injury. Trends Cardiovasc Med, 17(2):48-54.

[32]PestieauSR, QuezadoZMN, JohnsonYJ, et al., 2011. High-dose dexmedetomidine increases the opioid-free interval and decreases opioid requirement after tonsillectomy in children. Can J Anaesth, 58(6):540-550.

[33]QiYC, MaJ, LiSX, et al., 2019. Applicability of adipose-derived mesenchymal stem cells in treatment of patients with type 2 diabetes. Stem Cell Res Ther, 10:274.

[34]RazI, WexlerI, WeissO, et al., 2003. Role of insulin and the IGF system in renal hypertrophy in diabetic Psammomys obesus (sand rat). Nephrol Dial Transplant, 18(7):‍1293-1298.

[35]Ríos-SilvaM, TrujilloX, Trujillo-HernándezB, et al., 2014. Effect of chronic administration of forskolin on glycemia and oxidative stress in rats with and without experimental diabetes. Int J Med Sci, 11(5):448-452.

[36]SegevY, LandauD, MarbachM, et al., 1997. Renal hypertrophy in hyperglycemic non-obese diabetic mice is associated with persistent renal accumulation of insulin-like growth factor I. J Am Soc Nephrol, 8(3):436-444.

[37]SiYL, ZhaoYL, HaoHJ, et al., 2012. Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel role in improving insulin sensitivity. Diabetes, 61(6):1616-1625.

[38]SohnE, KimJ, KimCS, et al., 2015. Extract of Rhizoma Polygonum cuspidatum reduces early renal podocyte injury in streptozotocin‑induced diabetic rats and its active compound emodin inhibits methylglyoxal‑mediated glycation of proteins. Mol Med Rep, 12(4):5837-5845.

[39]TroibA, LandauD, YoungrenJF, et al., 2011. The effects of type 1 IGF receptor inhibition in a mouse model of diabetic kidney disease. Growth Horm IGF Res, 21(5):285-291.

[40]TurneyBW, KerrM, ChitnisMM, et al., 2012. Depletion of the type 1 IGF receptor delays repair of radiation-induced DNA double strand breaks. Radiother Oncol, 103(3):402-409.

[41]VasylyevaTL, FerryRJ, 2007. Novel roles of the IGF-IGFBP axis in etiopathophysiology of diabetic nephropathy. Diabetes Res Clin Pract, 76(2):177-186.

[42]WuHY, ZhangXC, JiaBB, et al., 2021. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate acetaminophen-induced acute liver failure through activating ERK and IGF-1R/PI3K/AKT signaling pathway. J Pharmacol Sci, 147(1):143-155.

[43]XiangE, HanB, ZhangQ, et al., 2020. Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy through inhibiting inflammation and fibrosis. Stem Cell Res Ther, 11:336.

[44]XieM, HaoHJ, ChengY, et al., 2017. Adipose-derived mesenchymal stem cells ameliorate hyperglycemia through regulating hepatic glucose metabolism in type 2 diabetic rats. Biochem Biophys Res Commun, 483(1):435-441.

[45]XieZY, HaoHJ, TongC, et al., 2016. Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats. Stem Cells, 34(3):627-639.

[46]XuYZ, FanP, LiuL, et al., 2023. Novel perspective in transplantation therapy of mesenchymal stem cells: TArgeting the ferroptosis pathway. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 24(2):115-129.

[47]YangS, ChintapalliJ, SodagumL, et al., 2005. Activated IGF-1R inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination. Am J Physiol Renal Physiol, 289(5):F1144-F1152.

[48]YapSK, TanKL, Abd RahamanNY, et al., 2022. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorated insulin resistance in type 2 diabetes mellitus rats. Pharmaceutics, 14(3):649.

[49]ZakariaEM, El-MaraghyNN, AhmedAF, et al., 2017. PARP inhibition ameliorates nephropathy in an animal model of type 2 diabetes: focus on oxidative stress, inflammation, and fibrosis. Naunyn-Schmiedeberg’s Arch Pharmacol, 390(6):621-631.

[50]ZhangYQ, LeX, ZhengS, et al., 2022. MicroRNA-146a-5p-modified human umbilical cord mesenchymal stem cells enhance protection against diabetic nephropathy in rats through facilitating M2 macrophage polarization. Stem Cell Res Ther, 13:171.

[51]ZhengS, ZhangK, ZhangYQ, et al., 2023. Human umbilical cord mesenchymal stem cells inhibit pyroptosis of renal tubular epithelial cells through miR-342-3p/caspase1 signaling pathway in diabetic nephropathy. Stem Cells Int, 2023:5584894.

[52]ZhouX, PatelD, SenS, et al., 2017. Poly-ADP-ribose polymerase inhibition enhances ischemic and diabetic wound healing by promoting angiogenesis. J Vasc Surg, 65(4):1161-1169.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE