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

doi:10.11958/20220420

Abstract

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

CLC Number:

R541.9，R542.2

Figures/Tables 7

References 22

[1]	WANG X, SHAPIRO J I. Evolving concepts in the pathogenesis of uraemic cardiomyopathy[J]. Nat Rev Nephrol, 2019, 15(3):159-175. doi:10.1038/s41581-018-0101-8.
[2]	KAESLER N, BABLER A, FLOEGE J, et al. Cardiac remodeling in chronic kidney disease[J]. Toxins (Basel), 2020, 12(3):161. doi:10.3390/toxins12030161.
[3]	RANGASWAMI J, BHALLA V, BLAIR J, et al. Cardiorenal syndrome:classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American Heart Association[J]. Circulation, 2019, 139(16):e840-e878. doi:10.1161/CIR.0000000000000664.
[4]	XUE J, SUAREZ J S, MINAAI M, et al. HMGB1 as a therapeutic target in disease[J]. J Cell Physiol, 2021, 236(5):3406-3419. doi:10.1002/jcp.30125.
[5]	MA X, ZHANG W, JIANG Y, et al. Paeoniflorin,a natural product with multiple targets in liver diseases-a mini review[J]. Front Pharmacol, 2020, 11:531. doi:10.3389/fphar.2020.00531.
[6]	SUNG I S, PARK S Y, JEONG K Y, et al. Investigation of the preventive effect of calcium on inflammation-mediated choroidal neovascularization[J]. Life Sci, 2019, 233:116727. doi:10.1016/j.lfs.2019.116727.
[7]	GAO R, ZHANG Y, KANG Y, et al. Glycyrrhizin inhibits PEDV infection and proinflammatory cytokine secretion via the HMGB1/TLR4-MAPK p38 Pathway[J]. Int J Mol Sci, 2020, 21(8):2961. doi:10.3390/ijms21082961.
[8]	ZHANG L, WANG F, WANG L, et al. Prevalence of chronic kidney disease in China:A cross-sectional survey[J]. Lancet, 2012, 379(9818):815-822. doi:10.1016/S0140-6736(12)60033-6.
[9]	SARNAK M J, AMANN K, BANGALORE S, et al. Chronic kidney disease and coronary artery disease:JACC state-of-the-art review[J]. J Am Coll Cardiol, 2019, 74(14):1823-1838. doi:10.1016/j.jacc.2019.08.1017.
[10]	YUAN J, ZOU X R, HAN S P, et al. Prevalence and risk factors for cardiovascular disease among chronic kidney disease patients: results from the Chinese cohort study of chronic kidney disease(C-STRIDE)[J]. BMC Nephrol, 2017, 18(1):23. doi:10.1186/s12882-017-0441-9.
[11]	JIN X, RONG S, YUAN W, et al. High Mobility Group Box 1 promotes aortic calcification in chronic kidney disease via the Wnt/β-Catenin pathway[J]. Front Physiol, 2018, 9:665. doi:10.3389/fphys.2018.00665.
[12]	RAUCCI A, DI MAGGIO S, SCAVELLO F, et al. The Janus face of HMGB1 in heart disease: a necessary update[J]. Cell Mol Life Sci, 2019, 76(2):211-229. doi:10.1007/s00018-018-2930-9.
[13]	谢美丽, 王越晖, 王智昊. 高迁移率族蛋白1与心血管疾病研究进展[J]. 国际老年医学杂志, 2021, 42(6):381-385.
	XIE M L, WANG Y H, WANG Z H. Advances in the Relationship between HMGB1 and Cardiovascular Diseases[J]. International Journal of Geriatrics, 2021, 42(6):381-385. doi:10.3969/j.issn.1674-7593.2021.06.015.
[14]	陈川斌, 黄锋. 高迁移率族蛋白1在心肌缺血再灌注损伤中作用的研究进展[J]. 天津医药, 2020, 48(11):1125-1130.
	CHEN C B, HUANG F. Research progress on the role of high mobility group box-1 in myocardial ischemia reperfusion injury[J]. Tianjin Med J, 2020, 48(11):1125-1130. doi:10.11958/20201796.
[15]	JIANG J, CHEN Q, CHEN X, et al. Magnesium sulfate ameliorates sepsis-induced diaphragm dysfunction in rats via inhibiting HMGB1/TLR4/NF-κB pathway[J]. Neuroreport, 2020, 31(12):902-908. doi:10.1097/WNR.0000000000001478.
[16]	HE M, BIANCHI M E, COLEMAN T R, et al. Exploring the biological functional mechanism of the HMGB1/TLR4/MD-2 complex by surface plasmon resonance[J]. Mol Med, 2018, 24(1):21. doi:10.1186/s10020-018-0023-8.
[17]	YANG H, WANG H, JU Z, et al. MD-2 is required for disulfide HMGB1-dependent TLR4 signaling[J]. J Exp Med, 2015, 212(1):5-14. doi:10.1084/jem.20141318.
[18]	XIONG X, GU L, WANG Y, et al. Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms[J]. J Neuroinflammation, 2016, 13(1):241. doi:10.1186/s12974-016-0705-5.
[19]	PAUDEL Y N, ANGELOPOULOU E, SEMPLE B, et al. Potential neuroprotective effect of the HMGB1 nnhibitor glycyrrhizin in neurological disorders[J]. ACS Chem Neurosci, 2020, 11(4):485-500. doi:10.1021/acschemneuro.9b00640.
[20]	CHEN H, GUAN B, WANG B, et al. Glycyrrhizin prevents hemorrhagic transformation and improves neurological outcome in ischemic stroke with delayed thrombolysis through targeting peroxynitrite-mediated HMGB1 signaling[J]. Transl Stroke Res, 2020, 11(5):967-982. doi:10.1007/s12975-019-00772-1.
[21]	ZHAI C L, ZHANG M Q, ZHANG Y, et al. Glycyrrhizin protects rat heart against ischemia-reperfusion injury through blockade of HMGB1-dependent phospho-JNK/Bax pathway[J]. Acta Pharmacol Sin, 2012, 33(12):1477-1487. doi:10.1038/aps.2012.112.
[22]	DU D, YAN J, REN J, et al. Synthesis, biological evaluation, and molecular modeling of glycyrrhizin derivatives as potent high-mobility group box-1 inhibitors with anti-heart-failure activity in vivo[J]. J Med Chem, 2013, 56(1):97-108. doi:10.1021/jm301248y.

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^＊＊