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何 阳,李其富,黎昌炫,陈瑞鹏.FGF21 / β-klotho / FGFR1 通路在 2 型糖尿病局灶性脑缺血模型大鼠脑损伤中的作用机制研究[J].中国比较医学杂志,2021,31(11):9~15.
FGF21 / β-klotho / FGFR1 通路在 2 型糖尿病局灶性脑缺血模型大鼠脑损伤中的作用机制研究
Mechanism of FGF21 / β-klotho / FGFR1 pathway in brain injury in type 2 diabetic model rats with focal cerebral ischemia
投稿时间:2020-12-21  
DOI:10. 3969 / j.issn.1671-7856. 2021. 11. 002
中文关键词:  2 型糖尿病  局灶性脑缺血  成纤维细胞生长因子 21 / β-klotho / 成纤维细胞生长因子 1 型受体通路
英文关键词:T2DM  focal cerebral ischemia  FGF21 / β-klotho / FGFR1 pathway
基金项目:
作者单位E-mail
何 阳 海南医学院第一附属医院 神经内科,海口 570000 hy91yh@ 163.com 
李其富 海南医学院第一附属医院 神经内科,海口 570000  
黎昌炫 海南医学院第一附属医院 神经内科,海口 570000  
陈瑞鹏 海南医学院第一附属医院 神经内科,海口 570000  
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中文摘要:
       目的 研究在 2 型糖尿病( T2DM) 局灶性脑缺血模型大鼠脑损伤中成纤维细胞生长因子 21 (FGF21) / β-klotho / 成纤维细胞生长因子 1 型受体(FGFR1)通路的作用。 方法 SD 大鼠采用高脂饲养结合腹腔链脲佐菌素(STZ)注射建立 T2DM 大鼠模型,采用线栓法建立大鼠大脑中动脉栓塞(MCAO)模型,实验分为正常对照组(Control 组)、单纯脑缺血组( MCAO 组)、T2DM 脑缺血组( T2DM +MCAO 组)、T2DM 脑缺血 FGFR1 抑制剂 PD173074 干预组(PD173074 组)及 T2DM 脑缺血 FGFR1 激动剂 PF05231023 干预组(PF05231023 组),每组 12 只, PD173074 组、PF05231023 组分别于 MCAO 术前 30 min 尾静脉注射 PD173074 5 mg / kg、PF05231023 5 mg / kg。 MCAO 24 h 后进行神经功能缺损评分,随后处死大鼠取脑组织标本。采用原位末端标记法(TUNEL)检测脑组织神经细胞凋亡,实时荧光定量 PCR(RT-qPCR) 检测脑组织 FGF21、β-klotho、FGFR1 mRNA 表达,免疫印迹( Western blot)检测脑组织 FGF21、β-klotho、FGFR1 蛋白及血小板内皮细胞粘附分子(CD31)、内皮素-1(ET-1)及血管内皮生长因子(VEGF)蛋白表达。 结果 与 Control 组比较,MCAO 组和 T2DM+MCAO 组大鼠神经功能缺损评分、神经细胞凋亡率、FGF21、β-klotho、FGFR1 mRNA 及蛋白水平、CD31、ET-1、VEGF 蛋白水平显著增加(P<0. 05);与 T2DM+ MCAO 组比较,PD173074 组大鼠神经功能缺损评分、神经细胞凋亡率、CD31、ET-1、VEGF 蛋白水平显著增加, FGF21、β-klotho、FGFR1 mRNA 及蛋白水平显著降低(P<0. 05),PF05231023 组大鼠神经功能缺损评分、神经细胞凋亡率、CD31、ET-1、VEGF 蛋白水平显著降低(P<0. 05),FGF21、β-klotho、FGFR1 mRNA 及蛋白水平显著增加(P< 0. 05)。 结论 FGF21 / β-klotho / FGFR1 通路激活可能在 T2DM 局灶性脑缺血模型大鼠中发挥重要保护作用。
英文摘要:
       Objective To investigate the mechanism of the fibroblast growth factor 21 ( FGF21) / β-klotho / fibroblast growth factor type 1 receptor (FGFR1) pathway in brain injury of type 2 diabetes mellitus (T2DM) model rats with focal cerebral ischemia. Methods SD rats were fed a high fat diet and injected intraperitoneally with streptozotocin (STZ) to establish the T2DM rat model. The middle cerebral artery occlusion ( MCAO) model was established by the suture method. Rats were divided into normal control group ( Control group), simple cerebral ischemia group ( MCAO group), T2DM cerebral ischemia group (T2DM + MCAO group), T2DM cerebral ischemia FGFR1 inhibitor PD173074 treatment group ( PD173074 group ) and T2DM cerebral ischemia FGFR1 agonist PF05231023 treatment group (PF05231023 group) with 12 rats in each group. PD173074 and PF05231023 groups were injected with 5 mg / kg PD173074 and 5 mg / kg PF05231023 respectively at 30 minutes before MCAO. After MCAO for 24 hours, the neurological deficit score was calculated and the rats were sacrificed to obtain brain tissue samples. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was used to detect neuronal apoptosis. Real-time quantitative PCR was used to detect mRNA expression of FGF21, β-klotho and FGFR1. Protein expression of FGF21, β-klotho, FGFR1, platelet endothelial cell adhesion molecule (CD31), endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) was detected by Western blot. Results Compared with the control group, the neurological deficit score, apoptosis rate of nerve cells, mRNA and protein levels of FGF21, β-klotho, FGFR1 and protein levels CD31, ET-1, VEGF were significantly increased in MCAO and T2DM + MCAO groups (P<0. 05). Compared with the T2DM + MCAO group, the neurological deficit score, apoptosis rate of nerve cells, protein levels of CD31, ET-1 and VEGF were increased in the PD173074 group, while the mRNA and protein levels of FGF21, β-klotho and FGFR1 were decreased (P< 0. 05). Moreover, the neurological deficit score, apoptosis rate of nerve cells and the protein levels of CD31, ET-1 and VEGF in the PF05231023 group were decreased, while the mRNA and protein levels of FGF21, β-klotho and FGFR1 were increased (P< 0. 05). Conclusions Activation of the FGF21 / β-klotho / FGFR1 pathway may play an important protective role in focal cerebral ischemia model rats with T2DM.
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