甘草酸对慢性肾脏病大鼠心肌HMGB1/TLR4/NF-κB/HIF-1α信号通路的影响

doi:10.11958/20220420

天津医药 ›› 2023, Vol. 51 ›› Issue (2): 155-159.doi: 10.11958/20220420

甘草酸对慢性肾脏病大鼠心肌HMGB1/TLR4/NF-κB/HIF-1α信号通路的影响

张雪(), 王家瑞, 陈康寅^△()

天津市心血管病离子与分子机能重点实验室，天津医科大学第二医院心脏科，天津心脏病学研究所（邮编300211）

收稿日期:2022-03-20 修回日期:2022-08-01 出版日期:2023-02-15 发布日期:2023-02-24
通讯作者: ^△E-mail：chenkangyin@vip.126.com
作者简介:张雪（1995），女，硕士在读，主要从事尿毒症心血管病方面研究。E-mail：z_x0219@163.com
基金资助:
天津市医学重点学科（专科）建设项目(TJYXZDXK-029A)

Effects of glycyrrhizin on myocardial HMGB1/TLR4/NF-κB/HIF-1α signaling pathway in chronic kidney disease rats

ZHANG Xue(), WANG Jiarui, CHEN Kangyin^△()

Tianjin Key Laboratory Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Cardiology, Tianjin 300211, China

Received:2022-03-20 Revised:2022-08-01 Published:2023-02-15 Online:2023-02-24
Contact: ^△E-mail：chenkangyin@vip.126.com

张雪, 王家瑞, 陈康寅. 甘草酸对慢性肾脏病大鼠心肌HMGB1/TLR4/NF-κB/HIF-1α信号通路的影响[J]. 天津医药, 2023, 51(2): 155-159.

ZHANG Xue, WANG Jiarui, CHEN Kangyin. Effects of glycyrrhizin on myocardial HMGB1/TLR4/NF-κB/HIF-1α signaling pathway in chronic kidney disease rats[J]. Tianjin Medical Journal, 2023, 51(2): 155-159.

摘要/Abstract

摘要：

目的探讨应用甘草酸（Gly）治疗时对慢性肾脏病（CKD）大鼠心室肌高迁移率族蛋白B1/Toll样受体4/核因子κB/缺氧诱导因子1α（HMGB1/TLR4/NF-κB/HIF-1α）信号通路的影响。方法将38只Wistar大鼠按随机数字表法分为4组：假手术（Sham）组、Sham+Gly组、CKD组、CKD+Gly组，5/6肾切除制备CKD模型，Gly腹腔注射给药（80 mg/kg）。4周后行血流动力学及心脏彩超观察各组大鼠心脏功能；心室取血检测生化指标；心肌组织取材检测HMGB1、TLR4、NF-κB、HIF-1α蛋白表达的变化。结果与Sham组相比，CKD组肌酐、尿酸、尿素氮和血清镁水平增高（P<0.05），血压升高，舒张期室间隔厚度、收缩期左心室内径增加，左心室射血分数降低，E/A比值降低，肺动脉血流加速时间延长（P<0.05）；HE染色可见心肌细胞肥大，Masson染色见心肌纤维化程度增加（P<0.05），心肌组织HMGB1、NF-κB、HIF-1α蛋白表达水平上调（P<0.05）。与CKD组相比，CKD+Gly组收缩期室间隔厚度增加，左心室射血分数升高，E/A比值升高（P<0.05），HE染色心肌细胞肥大情况有所好转，心肌纤维化程度降低（P<0.05），心肌组织HMGB1、NF-κB、HIF-1α蛋白表达水平下调（P<0.05）。结论 CKD会影响大鼠心功能，加重大鼠心肌纤维化，Gly可减轻CKD大鼠心肌纤维化程度，其机制可能与抑制HMGB1/TLR4/NF-κB/HIF-1α信号通路下传有关。

关键词: 甘草酸, 大鼠, Wistar, 慢性肾脏病, 心肌纤维化, HMGB1/TLR4/NF-κB/HIF-1α信号通路

Abstract:

Objective To investigate the effect of glycyrrhizin (Gly) treatment on high mobility group protein B1/ Toll-like receptor 4/ nuclear factor κB/ hypoxia-inducible factor 1α (HMGB1/TLR4/NF-κB/HIF-1α) signaling pathway on ventricular muscle of chronic kidney disease (CKD) rats. Methods A total of 38 Wistar rats were randomly divided into 4 groups: the sham operation (Sham) group, the Sham+ Gly group, the CKD group and the CKD+ Gly group. CKD model was prepared by nephrectomy in 5/6, and Gly was intraperitoneally injected (80 mg/kg). Four weeks later, hemodynamics and color doppler echocardiography were performed to observe the heart function of rats in each group. Ventricular blood sampling was used to detect biochemical indexes. The expression levels of HMGB1, TLR4, NF-κB and HIF-1α in myocardium were compared. Results Compared with the Sham group, creatinine, uric acid, urea nitrogen and serum magnesium were increased in the CKD group (P<0.05), blood pressure was also increased (P<0.05). Besides, its diastolic ventricular septal thickness, left ventricular end-systolic diameter were increased, left ventricular ejection fraction decreased, E/A peak decreased and pulmonary artery acceleration time was prolonged (P<0.05). HE staining showed hypertrophy of myocardial cells, and Masson staining showed increased degree of myocardial fibrosis (P<0.05). The expression levels of HMGB1, NF-κB and HIF-1α in myocardial tissue were up-regulated (P<0.05). Compared with the CKD group, rats in the CKD+Gly group showed increased ventricular septal thickness, left ventricular ejection fraction and E/A ratio (P<0.05). HE staining showed that the hypertrophy of myocardial cells was improved, and the degree of myocardial fibrosis decreased (P<0.05). The expression levels of HMGB1, NF-κB and HIF-1α in myocardium were down-regulated (P<0.05). Conclusion CKD can affect cardiac function and aggravate myocardial fibrosis in rats. Glycyrrhizin can improve the degree of myocardial fibrosis in rats with CKD, and the mechanism may be related to the inhibition of HMGB1/TLR4/NF-κB/HIF-1α signaling pathway.

Key words: glycyrrhizic acid, rats, Wistar, chronic kidney disease, myocardial fibrosis, HMGB1/TLR4/NF-κB/HIF-1α signaling pathway

中图分类号:

R541.9，R542.2

图/表 7

参考文献 22

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组别	肌酐（μmol/L）		尿酸（μmol/L）		尿素氮（mmol/L）		血清镁（mmol/L）
Sham组	20.16±9.62		16.43±5.65		6.15±0.53		0.75±0.06
Sham+Gly组	25.35±5.39		24.15±16.07		6.45±0.59		0.87±0.18^a
CKD组	47.53±9.22^ab		59.84±12.49^ab		12.87±1.92^ab		1.11±0.10^ab
CKD+Gly组	44.32±9.23^ab		54.08±21.96^ab		13.21±3.13^ab		1.12±0.13^ab
F	22.514^＊＊		16.478^＊＊		33.016^＊＊		19.717^＊＊
组别		心脏质量（g）		体质量（g）		心脏体质量比（%）
Sham组		1.13±0.17		351.75±28.50		0.32±0.03
Sham+Gly组		1.27±0.15		389.50±38.51		0.33±0.01
CKD组		1.21±0.09		348.75±18.72		0.35±0.02
CKD+Gly组		1.29±0.19		332.67±46.31		0.39±0.04^ab
F		1.005		1.973		5.266^＊

组别	肌酐（μmol/L）		尿酸（μmol/L）		尿素氮（mmol/L）		血清镁（mmol/L）
Sham组	20.16±9.62		16.43±5.65		6.15±0.53		0.75±0.06
Sham+Gly组	25.35±5.39		24.15±16.07		6.45±0.59		0.87±0.18^a
CKD组	47.53±9.22^ab		59.84±12.49^ab		12.87±1.92^ab		1.11±0.10^ab
CKD+Gly组	44.32±9.23^ab		54.08±21.96^ab		13.21±3.13^ab		1.12±0.13^ab
F	22.514^＊＊		16.478^＊＊		33.016^＊＊		19.717^＊＊
组别		心脏质量（g）		体质量（g）		心脏体质量比（%）
Sham组		1.13±0.17		351.75±28.50		0.32±0.03
Sham+Gly组		1.27±0.15		389.50±38.51		0.33±0.01
CKD组		1.21±0.09		348.75±18.72		0.35±0.02
CKD+Gly组		1.29±0.19		332.67±46.31		0.39±0.04^ab
F		1.005		1.973		5.266^＊

组别	心率（次/min）	收缩压（mmHg）	平均动脉压（mmHg）	舒张压（mmHg）
Sham组	406.84±25.63	129.03±9.92	109.65±7.83	99.80±7.98
Sham+Gly组	401.78±32.92	138.95±19.00	114.63±17.54	102.07±17.75
CKD组	421.09±42.17	154.30±13.68^ab	125.59±12.80^a	111.10±13.12
CKD+Gly组	408.59±36.40	149.86±15.80^a	124.47±14.49^a	111.31±15.16
F	0.497	5.137^＊＊	2.905^＊	1.684

组别	心率（次/min）	收缩压（mmHg）	平均动脉压（mmHg）	舒张压（mmHg）
Sham组	406.84±25.63	129.03±9.92	109.65±7.83	99.80±7.98
Sham+Gly组	401.78±32.92	138.95±19.00	114.63±17.54	102.07±17.75
CKD组	421.09±42.17	154.30±13.68^ab	125.59±12.80^a	111.10±13.12
CKD+Gly组	408.59±36.40	149.86±15.80^a	124.47±14.49^a	111.31±15.16
F	0.497	5.137^＊＊	2.905^＊	1.684

组别	舒张期室间隔厚度（mm）	收缩期室间隔厚度（mm）	舒张期左心室内径（mm）	收缩期左心室内径（mm）	舒张期左心室后壁厚度（mm）	收缩期左心室后壁厚度（mm）	左心室射血分数	E/A	肺动脉血流加速时间（ms）
Sham组	1.83±0.28	2.94±0.36	6.54±0.63	3.26±0.81	2.01±0.28	3.52±0.57	0.81±0.07	1.34±0.28	25.32±2.00
Sham+Gly组	2.06±0.24	3.21±0.47	6.76±0.30	3.86±0.47	2.10±0.25	3.54±0.47	0.76±0.07^a	1.19±0.05	25.38±4.67
CKD组	2.08±0.23^a	2.93±0.31	6.65±0.58	4.37±1.06^a	2.32±0.48	3.54±0.51	0.62±0.11^ab	0.84±0.11^ab	34.43±5.98^ab
CKD+Gly组	2.21±0.17^a	3.49±0.44^ac	6.50±0.65	3.85±0.67	2.37±0.43	3.61±0.34	0.70±0.08^ac	1.14±0.20^c	31.66±5.62^ab
F	4.653^＊＊	4.693^＊＊	0.401	2.931^＊	1.839	0.075	8.093^＊＊	11.010^＊＊	7.635^＊＊

甘草酸对慢性肾脏病大鼠心肌HMGB1/TLR4/NF-κB/HIF-1α信号通路的影响

Effects of glycyrrhizin on myocardial HMGB1/TLR4/NF-κB/HIF-1α signaling pathway in chronic kidney disease rats

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组别	HMGB1	TLR4	NF-κB	HIF-1α
Sham组	0.93±0.12	1.03±0.07	0.97±0.06	1.03±0.07
Sham+Gly组	1.12±0.17	1.08±0.10	1.01±0.21	1.13±0.12
CKD组	2.38±0.31^ab	1.14±0.13	3.54±0.24^ab	2.30±0.17^ab
CKD+Gly组	1.93±0.59^abc	1.03±0.09	1.57±0.22^abc	1.82±0.16^abc
F	40.287^＊＊	0.799	111.536^＊＊	57.732^＊＊

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