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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

[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.