甲基莲心碱调节SDF-1/CXCR4信号通路对糖尿病肾病的影响

doi:10.3969/j.issn.1674-8115.2024.02.004

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (2): 183-195.doi: 10.3969/j.issn.1674-8115.2024.02.004

• 论著 · 基础研究 • 上一篇

甲基莲心碱调节SDF-1/CXCR4信号通路对糖尿病肾病的影响

王莹¹(), 平立风², 刘彤彤³, 刘珊珊⁴, 刘磊¹()

^1.山东第一医科大学第二附属医院内分泌科，泰安 271000
^2.山东第一医科大学第二附属医院全科医学科，泰安 271000
^3.山东第一医科大学第二附属医院心血管内科，泰安 271000
^4.山东省泰安市中心医院妇科，泰安 271000

收稿日期:2023-04-13 接受日期:2023-11-30 出版日期:2024-02-28 发布日期:2024-03-25
通讯作者: 刘磊 E-mail:taiyiwangying2009@163.com;2625260425@qq.com
作者简介:王莹（1986—），女，副主任医师，硕士；电子信箱：taiyiwangying2009@163.com。
基金资助:
山东省高等学校科技计划项目(J17KA246)

Effect of neferine on diabetic nephropathy by regulating SDF-1/CXCR4 signal pathway

WANG Ying¹(), PING Lifeng², LIU Tongtong³, LIU Shanshan⁴, LIU Lei¹()

^1.Endocrinology Department, The Second Affiliated Hospital of Shandong First Medical University, Tai'an 271000, China
^2.Medical Category, The Second Affiliated Hospital of Shandong First Medical University, Tai'an 271000, China
^3.Cardiovascular Department, The Second Affiliated Hospital of Shandong First Medical University, Tai'an 271000, China
^4.Department of Gynaecology, Tai'an City Central Hospital of Shandong Province, Tai'an 271000, China

Received:2023-04-13 Accepted:2023-11-30 Online:2024-02-28 Published:2024-03-25
Contact: LIU Lei E-mail:taiyiwangying2009@163.com;2625260425@qq.com
Supported by:
Project of Science and Technology Plan of Institution of Higher Learning in Shandong Province(J17KA246)

摘要/Abstract

摘要：

目的·探讨甲基莲心碱（neferine，Nef）对糖尿病肾病（diabetic nephropathy，DN）大鼠肾组织的作用及其相关机制。方法·采用高脂饲料喂食联合腹腔注射链脲佐菌素的方法构建DN模型大鼠，并将造模成功的大鼠随机分为DN组、Nef（低、中、高）剂量组、Nef高剂量+通路拮抗剂（AMD3100）组，每组10只。同时，选10只普通大鼠作为正常组。检测6组大鼠的空腹血糖（fasting blood glucose，FBG）、24 h尿蛋白、血清糖化血红蛋白（glycosylated hemoglobin，HbA1c）、血清肌酐（serum creatinine，Scr）、尿素氮（blood urea nitrogen，BUN）水平及肾指数。分别采用苏木精-伊红（hematoxylin-eosin，H-E）染色、马松（Masson）染色观察6组大鼠的肾组织的病理变化。采用硫代巴比妥酸（thiobarbituric acid，TBA）法检测肾组织丙二醛（malondialdehyde，MDA）含量，分别采用水溶性四氮唑（water soluble tetrazolium，WST-1）法、钼酸铵法检测肾组织超氧化物歧化酶（superoxide dismutase，SOD）、过氧化氢酶（catalase，CAT）的活性。分别采用实时荧光定量PCR（quantitative real-time PCR，qPCR）和蛋白质印迹法（Western blotting）检测肾组织中基质细胞衍生因子-1（stromal cell-derived factor-1，SDF-1）、CXC趋化因子受体4（CXC chemokine receptor 4，CXCR4）的mRNA以及蛋白表达。采用高糖（30 mmol/L葡萄糖）诱导大鼠肾小管上皮细胞NRK-52E，以建立DN细胞模型。将该细胞分为对照组、高糖（HG）组、HG+Nef（低、中、高）剂量组（即HG+Nef-L、M、H组）、HG+Nef-H+AMD3100组。分别采用WST-1法、钼酸铵法检测模型细胞中SOD、CAT活性，采用TBA法检测MDA含量，分别采用qPCR、Western blotting检测SDF-1、CXCR4的mRNA及蛋白表达，采用CCK-8法、流式细胞术检测细胞活力和凋亡率。结果·与DN组比较，Nef（低、中、高）剂量组和Nef高剂量+AMD3100组大鼠的FBG、24 h尿蛋白、HbA1c、Scr、BUN水平以及肾指数、MDA水平均较低，SDF-1、CXCR4的mRNA和蛋白表达以及SOD、CAT活性均较高（均P<0.05），肾组织病理损伤、纤维化程度有所减轻，且均呈剂量依赖性；AMD3100能减弱高剂量Nef对DN大鼠的肾保护作用。与HG组比较，HG+Nef-L、M、H组NRK-52E细胞的活力，SOD、CAT活性，SDF-1、CXCR4的mRNA和蛋白表达均较高，MDA含量及凋亡率均较低（均P<0.05）；AMD3100可逆转Nef-H对NRK-52E细胞损伤的保护作用。结论·Nef可能通过激活SDF-1/CXCR4信号通路来控制DN大鼠的血糖水平并提高其抗氧化能力，从而发挥肾保护作用。

关键词: 糖尿病肾病, 甲基莲心碱, 肾脏, 基质细胞衍生因子-1/CXC趋化因子受体4信号通路

Abstract:

Objective ·To investigate the effect of neferine (Nef) on renal tissues of diabetic nephropathy (DN) rats and its related mechanism. Methods ·DN model rats were constructed by feeding high-fat diet combined with intraperitoneal injection of streptozotocin, and the successfully constructed rats were randomly divided into DN group, Nef (low, medium and high) dose groups and Nef high-dose+pathway antagonist (AMD3100) group, with 10 rats in each group. At the same time, 10 common rats were selected as the normal group. The levels of fasting blood glucose (FBG), 24 h urinary protein, serum glycosylated hemoglobin (HbA1c), serum creatinine (Scr), blood urea nitrogen (BUN) and renal index of rats in the six groups were measured. Hematoxylin-eosin (H-E) and Masson staining were used to observe the pathological changes of renal tissues. The content of malondialdehyde (MDA) in renal tissues was determined by thiobarbituric acid (TBA) method, and the activities of superoxide dismutase (SOD) and catalase (CAT) in renal tissues were determined by water soluble tetrazolium (WST-1) method and ammonium molybdate method, respectively. The mRNA and protein expressions of stromal cell-derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) in renal tissues were detected by quantitative real-time PCR (qPCR) and Western blotting, respectively. Rat renal tubular epithelium cells NRK-52E were induced by high glucose (30 mmol/L glucose) to establish DN cell model. The cells were divided into control group, high glucose (HG) group, HG+Nef (low, medium and high) dose (i.e.HG+Nef-L, M and H) group, and HG+Nef-H +AMD3100 group. SOD and CAT activities were detected by WST-1 method and ammonium molybdate method, respectively. MDA content was detected by TBA method. The mRNA and protein expressions of SDF-1 and CXCR4 were detected by qPCR and Western blotting, respectively. CCK-8 method and flow cytometry were used to detect cell viability and apoptosis rate, respecti-vely. Results ·Compared with the DN group, the levels of FBG, 24 h urinary protein, HbA1c, Scr, BUN, renal index and MDA content in Nef (low, medium and high) dose groups and Nef high-dose+AMD3100 group were decreased, the mRNA and protein expressions of SDF-1 and CXCR4 were increased, and the activities of SOD and CAT were increased (all P<0.05). The degree of pathological damage and fibrosis of renal tissues was reduced; all of the above changes were dose-dependent. AMD3100 could weaken the renal protective effect of high-dose Nef on DN rats. Compared with the HG group, NRK-52E cell viability, SOD and CAT activities, and the mRNA and protein expressions of SDF-1 and CXCR4 were increased in HG+Nef-L, M and H groups, while apoptosis rate and MDA content were decreased (all P<0.05). AMD3100 could reverse the protective effect of Nef-H on NRK-52E cell damage. Conclusion ·Nef may control blood glucose levels on DN rats and improve antioxidant capacity by activating the SDF-1/CXCR4 signal pathway, playing a renal protective role.

Key words: diabetic nephropathy (DN), neferine (Nef), renal, stromal cell-derived factor-1/CXC chemokine receptor 4 signal pathway

中图分类号:

R587.2

王莹, 平立风, 刘彤彤, 刘珊珊, 刘磊. 甲基莲心碱调节SDF-1/CXCR4信号通路对糖尿病肾病的影响[J]. 上海交通大学学报（医学版）, 2024, 44(2): 183-195.

WANG Ying, PING Lifeng, LIU Tongtong, LIU Shanshan, LIU Lei. Effect of neferine on diabetic nephropathy by regulating SDF-1/CXCR4 signal pathway[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(2): 183-195.

图/表 12

表 1 qPCR引物序列

Tab 1 Primer sequence for qPCR

Primer	Forward sequence (5'→3')	Reverse sequence (5'→3')
Sdf-1	GACGGTAAGCCAGTCAGCCT	CAGGTACCTCTGGATCCACT
Cxcr4	ACGCACGACGTCTTCCAGTA	CCACCTGGTTCAACTCACTCC
β-actin	GCACCACACCTTCTACAATG	TGCTTGCTGATCCACATCTG

图1 各组大鼠FBG、24 h尿蛋白水平比较Note： A. FBG level. B. 24 h urinary protein level. ①P=0.000, compared with the normal group; ②P=0.000, compared with the DN group; ③P=0.000, compared with the Nef low-dose group; ④P=0.000, compared with the Nef medium-dose group; ⑤P=0.000, compared with the Nef high-dose group.

Fig 1 Comparison of the FBG and 24 h urinary protein levels of rats in each group

图2 各组大鼠血清HbA1c、Scr、BUN水平及肾指数比较Note： A. Serum HbA1c levels. B. Scr levels. C. BUN levels. D. Renal index. ①P=0.000, compared with the normal group; ②P=0.000, compared with the DN group; ③P=0.000, compared with the Nef low-dose group; ④P=0.000, compared with the Nef medium-dose group; ⑤P=0.000, compared with the Nef high-dose group.

Fig 2 Comparison of the serum HbA1c, Scr, BUN levels and renal index of rats in each group

图3 各组大鼠肾组织的病理形态观察 (H-E staining, ×200)Note： Blue arrows indicate glomerular hypertrophy; yellow arrows indicate vacuolar degeneration of renal tubular epithelial cells.

Fig 3 Observation of the pathological morphology of the renal tissues of rats in each group (H-E staining, ×200)

图4 各组大鼠肾组织的纤维化观察 (Masson staining, ×200)

Fig 4 Observation of renal tissue fibrosis of rats in each group (Masson staining, ×200)

图5 各组大鼠肾组织中MDA含量及SOD、CAT活性比较Note： A. MDA content. B. SOD activity. C. CAT activity. ①P=0.000, compared with the normal group; ②P=0.000, compared with the DN group; ③P=0.000, compared with the Nef low-dose group; ④P=0.000, compared with the Nef medium-dose group; ⑤P=0.000, compared with the Nef high-dose group.

Fig 5 Comparison of MDA content and SOD, CAT activity in renal tissues of rats in each group

图6 各组大鼠肾组织中 Sdf-1 、 Cxcr4 mRNA表达比较Note： A. Relative expression of Sdf-1 mRNA. B. Relative expression of Cxcr4 mRNA. ①P=0.000, compared with the normal group; ②P=0.000, compared with the DN group; ③P=0.000, compared with the Nef low-dose group; ④P=0.000, compared with the Nef medium-dose group; ⑤P=0.000, compared with the Nef high-dose group.

Fig 6 Comparison of Sdf-1 and Cxcr4 mRNA expression in renal tissues of rats in each group

图7 各组大鼠肾组织中SDF-1、CXCR4蛋白表达Note： A. Western blotting analysis of SDF-1 and CXCR4 protein expression. B/C. Statistical analysis of relative expression of SDF-1 protein (B) and CXCR4 protein (C). ①P=0.000, compared with the normal group; ②P=0.000, compared with the DN group; ③P=0.000, compared with the Nef low-dose group; ④P=0.000, compared with the Nef medium-dose group; ⑤P=0.000, compared with the Nef high-dose group.

Fig 7 SDF-1 and CXCR4 protein expression in renal tissues of rats in each group

图8 各组NRK-52E细胞中MDA含量及SOD、CAT活性比较Note： A. MDA content. B. SOD activity. C. CAT activity. ①P=0.000, compared with the control group; ②P=0.000, compared with the HG group; ③P=0.000, compared with the HG+Nef-L group; ④P=0.000, compared with the HG+Nef-M group; ⑤P=0.000, compared with the HG+Nef-H group.

Fig 8 Comparison of MDA content and SOD, CAT activity in NRK-52E cells of each group

图9 各组NRK-52E细胞中 Sdf-1 、 Cxcr4 mRNA表达比较Note： A. Relative expression of Sdf-1 mRNA. B. Relative expression of Cxcr4 mRNA. ①P=0.000, compared with the control group; ②P=0.000, compared with the HG group; ③P=0.000, compared with the HG+Nef-L group; ④P=0.000, compared with the HG+Nef-M group; ⑤P=0.000, compared with the HG+Nef-H group.

Fig 9 Comparison of Sdf-1 and Cxcr4 mRNA expression in NRK-52E cells of each group

图10 各组NRK-52E细胞中SDF-1、CXCR4蛋白表达Note： A. Western blotting analysis of SDF-1 and CXCR4 protein expression. B/C. Statistical analysis of relative expression of SDF-1 protein (B) and CXCR4 protein (C). ①P=0.000, compared with the control group; ②P=0.000, compared with the HG group; ③P=0.000, compared with the HG+Nef-L group; ④P=0.000, compared with the HG+Nef-M group; ⑤P=0.000, compared with the HG+Nef-H group.

Fig 10 SDF-1 and CXCR4 protein expression in NRK-52E cells of each group

图11 各组NRK-52E细胞的活力及凋亡率比较Note： A. Detection of cell apoptosis by flow cytometry. B. Statistical analysis of cell viability. C. Statistical analysis of cell apoptosis rate. ①P=0.000, compared with the control group; ②P=0.000, compared with the HG group; ③P=0.000, compared with the HG+Nef-L group; ④P=0.000, compared with the HG+Nef-M group; ⑤P=0.000, compared with the HG+Nef-H group.

Fig 11 Comparison of NRK-52E cell activity and apoptosis rate in each group

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甲基莲心碱调节SDF-1/CXCR4信号通路对糖尿病肾病的影响

Effect of neferine on diabetic nephropathy by regulating SDF-1/CXCR4 signal pathway

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