槲皮素通过抑制HMGB1/RAGE/NF-κB信号通路减轻糖尿病引起的大鼠肾脏损伤

doi:10.12122/j.issn.1673-4254.2024.09.17

南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (9): 1769-1775.doi: 10.12122/j.issn.1673-4254.2024.09.17

槲皮素通过抑制HMGB1/RAGE/NF-κB信号通路减轻糖尿病引起的大鼠肾脏损伤

姜一凡¹(), 李小荣², 耿嘉逸³, 陈永锋², 唐碧²(), 康品方²^,⁴()

^1.蚌埠医科大学，临床医学院临床医学专业，安徽蚌埠 233000
^2.蚌埠医科大学，第一附属医院心血管科，安徽蚌埠 233000
^3.蚌埠医科大学，精神卫生学院精神医学专业，安徽蚌埠 233000
^4.蚌埠医科大学，心脑血管基础与临床重点实验室，安徽蚌埠 233000

收稿日期:2023-12-20 出版日期:2024-09-20 发布日期:2024-10-31
通讯作者: 唐碧,康品方 E-mail:3173260851@qq.com;bitang2000@163.com;kangpinfang.1016@163.com
作者简介:姜一凡，E-mail: 3173260851@qq.com
基金资助:
国家自然科学基金(81970313);安徽省自然科学基金青年项目(1908085QH353);安徽省教育厅优秀青年项目(2022AH030141);安徽省教育厅优秀创新团队(2022AH010083);安徽省临床转化专项青年项目(20230429510 7020087);蚌埠医科大学大学生创新创业课题(bydc2022031)

Quercetin ameliorates diabetic kidney injury in rats by inhibiting the HMGB1/RAGE/ NF-κB signaling pathway

Yifan JIANG¹(), Xiaorong LI², Jiayi GENG³, Yongfeng CHEN², Bi TANG²(), Pinfang KANG²^,⁴()

^1.School of Clinical Medicine,
^2.Department of Cardiovascular Medicine of First Affiliated Hospital,
^3.School of Psychiatric Medicine, School of Mental Health,
^4.Key Laboratory of Preclinical and Clinical Research of Cardiovascular and cerebrovascular Diseases, Bengbu Medical University, Bengbu 233000, China

Received:2023-12-20 Online:2024-09-20 Published:2024-10-31
Contact: Bi TANG, Pinfang KANG E-mail:3173260851@qq.com;bitang2000@163.com;kangpinfang.1016@163.com
Supported by:
National Natural Science Foundation of China(81970313)

摘要/Abstract

摘要：

目的探究槲皮素对链脲佐菌素（STZ）致糖尿病大鼠的肾脏炎症反应和细胞凋亡的影响及其可能的机制。方法采取腹腔一次性注射STZ建立糖尿病SD大鼠模型，并设置正常对照组（NC组，n=6）、高糖高脂组（HC组，n=6）、糖尿病模型组（DM组，n=6）、槲皮素组（DMQ组，n=6），DMQ组每日给予100 mg/kg的槲皮素灌胃处理。通过HE染色观察肾组织的病理学形态变化；ELISA检测血清炎症反应；免疫组化观察NF-κB的表达情况；血糖分析仪检测FBG；磷酸甘油氧化酶法、脲酶法、肌氨酸酶氧化酶法、双缩脲法等方法测定各组大鼠血清TG、BUN、Scr含量以及24 h尿蛋白含量；Western blotting检测各组大鼠肾脏组织HMGB1、RAGE、NF-κB、Bax、Bcl-2、Caspase-3的表达情况。结果与正常对照组相比，糖尿病组大鼠FBG、TG、BUN、Scr、肾脏肥大指数和24 h尿蛋白均显著升高（P<0.01）；血清炎症因子IL-1β、IL-6和TNF-α水平显著升高（P<0.01）；肾脏结构产生典型的病理性变化；肾脏组织HMGB1、RAGE、NF-κB、Bax、Caspase-3的表达量明显升高（P<0.01），Bcl-2的表达量明显降低（P<0.01）。与糖尿病组相比，经过槲皮素干预后上述情况得到相反的结果。结论槲皮素能够改善糖尿病引起的肾脏损伤，其保护作用可能与抑制HMGB1/RAGE/NF-κB炎症信号通路，进而减轻肾脏的炎症反应、细胞凋亡等。

关键词: 槲皮素, 糖尿病肾病, HMGB1/RAGE/NF-κB信号通路

Abstract:

Objective To explore the effect of quercetin on renal inflammation and cell apoptosis in diabetic rats and its possible mechanisms. Methods Twenty-four adult male SD rats were randomized equally into normal control group, high-glucose and high-fat feeding group, streptozotocin (STZ)-induced diabetic model group, and quercetin treatment (daily dose 100 mg/kg) group. Pathological changes of the renal tissues of the rats were observed with HE staining, serum inflammatory factor levels were determined with ELISA, and renal expression of NF‑κB was observed by immunohistochemistry. Fast blood glucose (FBG), serum levels of triglyceride (TG), BUN, and Scr, and 24-h urine protein content of the rats were measured, and renal expressions of HMGB1, RAGE, NF‑κB, Bax, Bcl-2, and caspase-3 were detected with Western blotting. Results The diabetic rats showed significantly increased levels of FBG, TG, BUN, and Scr, renal hypertrophy index, 24-h urinary protein content, serum IL-1β, IL-6 and TNF-α levels and renal expressions HMGB1, RAGE, NF‑κB, Bax, and caspase-3 with decreased renal expression of Bcl-2. All these changes were significantly alleviated by quercetin treatment of the rats. Conclusion Quercetin can ameliorate kidney injury in diabetic rats possibly by inhibiting the HMGB1/RAGE/NF-κB inflammatory signaling pathway to reduce renal inflammation and renal cell apoptosis.

Key words: quercetin, diabetic nephropathy, HMGB1/ RAGE/ NF-κB signaling pathway

姜一凡, 李小荣, 耿嘉逸, 陈永锋, 唐碧, 康品方. 槲皮素通过抑制HMGB1/RAGE/NF-κB信号通路减轻糖尿病引起的大鼠肾脏损伤[J]. 南方医科大学学报, 2024, 44(9): 1769-1775.

Yifan JIANG, Xiaorong LI, Jiayi GENG, Yongfeng CHEN, Bi TANG, Pinfang KANG. Quercetin ameliorates diabetic kidney injury in rats by inhibiting the HMGB1/RAGE/ NF-κB signaling pathway[J]. Journal of Southern Medical University, 2024, 44(9): 1769-1775.

图/表 6

表1 各组大鼠血液中FBG、TG的比较

Tab.1 Comparisons of fasting blood glucose (FBG) and triglyceride (TG) among the groups (Mean±SD, n=6)

Group	FBG (mmol/L)	TG (mmol/L)
NC	5.88±0.51	0.96±0.16
HC	5.80±0.33	1.48±0.19**
DM	26.67±5.65**	3.82±0.35**
DMQ	19.28±1.45^##	2.95±0.29^##

表2 各组大鼠血液中BUN、Scr、24 h尿蛋白和肾脏肥大指数比较

Tab.2 Comparison of blood urea nitrogen (BUN), serum creatinine (Scr), 24-hour urinary protein level (24 h-UP) and renal hypertrophy index (RHI) among the groups (Mean±SD, n=6 )

Group	BUN (mmol/L)	Scr (μmol/L)	24 h-UP (mg/24 h)	RHI (×10^-³)
NC	8.11±0.45	35.9±2.4	16.03±2.04	5.3±0.3
HC	15.4±0.68**	45.9±3.3**	36.25±3.20**	6.7±0.5
DM	18.45±0.30**	59.1±3.1**	65.42±3.59**	14.6±0.6**
DMQ	12.51±0.25^##	44.9±3.1^##	42.74±5.96^##	9.6±0.8^##

图1 各组大鼠血清炎症因子IL-1β、IL-6和TNF-α表达水平的比较

Fig.1 Comparisons of serum levels of IL-1β (A), IL-6 (B) and TNF-α (C) among the groups (Mean±SD, n=6). **P<0.01 vs NC group, ##P<0.01 vs DM group.

图2 各组大鼠肾组织HE染色结果的比较

Fig.2 HE staining of rat kidney tissues in each group. A: NC group; B: HC group; C: DM group; D: DMQ group.

图3 各组大鼠肾组织NF-κB免疫组化结果以及HMGB1、RAGE、NF-κB蛋白表达水平的比较

Fig.3 Immunohistochemical results of NF-κB and relative protein expressions of HMGB1, RAGE and NF-κB in rat kidney tissues in each group (Mean±SD, n=4). A, B: Immunohistochemical results for NF-κB and quantitative analysis of its expression levels (a: NC group; b: HC group; c: DM group; d: DMQ group). C: Western blotting results of HMGB1, RAGE, NF-κB and GAPDH. D-F: HMGB1, RAGE and NF-κB protein levels normalized by GAPDH levels. **P<0.01 vs NC group; ##P<0.01 vs DM group.

图4 各组大鼠肾组织Bax、Bcl-2和Caspase-3表达水平的比较

Fig.4 Comparisons of relative protein expressions of Bax, Bcl-2 and caspase-3 in rat kidney tissues among the groups (Mean±SD, n=4). A: Western blotting results of Bax, Bcl-2, caspase-3 and GAPDH. B, C: Bax/Bcl-2 and caspase-3 protein levels normalized by GAPDH levels. **P<0.01 vs NC group; ##P<0.01 vs DM group.

参考文献 32

1	Tuttle KR, Brosius FC 3rd, Cavender MA, et al. SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the national kidney foundation[J]. Am J Kidney Dis, 2021, 77(1): 94-109.
2	Yang C, Wang HB, Zhao XJ, et al. CKD in China: evolving spectrum and public health implications[J]. Am J Kidney Dis, 2020, 76(2): 258-64.
3	Tuttle KR, Cherney DZI. Therapeutic transformation for diabetic kidney disease[J]. Kidney Int, 2021, 99(2): 301-3.
4	Pezzolesi MG, Krolewski AS. The genetic risk of kidney disease in type 2 diabetes[J]. Med Clin North Am, 2013, 97(1): 91-107.
5	Alouffi S, Khan MWA. Dicarbonyls generation, toxicities, detoxifications and potential roles in diabetes complications[J]. Curr Protein Pept Sci, 2020, 21(9): 890-8.
6	Noels H, Lehrke M, Vanholder R, et al. Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations[J]. Nat Rev Nephrol, 2021, 17(8): 528-42.
7	Calle P, Hotter G. Macrophage phenotype and fibrosis in diabetic nephropathy[J]. Int J Mol Sci, 2020, 21(8): 2806.
8	Jaikumkao K, Thongnak L, Htun KT, et al. Dapagliflozin and metformin in combination ameliorates diabetic nephropathy by suppressing oxidative stress, inflammation, and apoptosis and activating autophagy in diabetic rats[J]. Biochim Biophys Acta Mol Basis Dis, 2024, 1870(1): 166912.
9	Pérez-Morales RE, Del Pino MD, Valdivielso JM, et al. Inflammation in diabetic kidney disease[J]. Nephron, 2019, 143(1): 12-6.
10	Rayego-Mateos S, Morgado-Pascual JL, Opazo-Ríos L, et al. Pathogenic pathways and therapeutic approaches targeting inflammation in diabetic nephropathy[J]. Int J Mol Sci, 2020, 21(11): 3798.
11	Wu M, Han WX, Song S, et al. NLRP3 deficiency ameliorates renal inflammation and fibrosis in diabetic mice[J]. Mol Cell Endocrinol, 2018, 478: 115-25.
12	魏思灿, 林天来, 黄玲, 等. 槲皮素通过PINK1/parkin通路激活线粒体自噬减轻大鼠脑缺血再灌注损伤[J]. 中国病理生理杂志, 2020, 36(12): 2251-7.
13	Chai GR, Liu S, Yang HW, et al. Quercetin protects against diabetic retinopathy in rats by inducing heme oxygenase-1 expression[J]. Neural Regen Res, 2021, 16(7): 1344-50.
14	Li XY, Chen RM, Lei XT, et al. Quercetin regulates ERα mediated differentiation of BMSCs through circular RNA[J]. Gene, 2021, 769: 145172.
15	王建礼, 杨作成, 王聪, 等. 槲皮素对糖尿病大鼠的降糖作用及机制研究[J]. 济宁医学院学报, 2018, 41(2): 135-8.
16	Wang S, Du SS, Wang WZ, et al. Therapeutic investigation of quercetin nanomedicine in a zebrafish model of diabetic retinopathy[J]. Biomedecine Pharmacother, 2020, 130: 110573.
17	高啸, 沈莹. HMGB1-RAGE/TLRs-NF-κB信号通路中关键蛋白的表达与糖尿病肾病的关系[J]. 转化医学杂志, 2020, 9(6): 331-4, 339.
18	黄小翠，于赵龙，祝子健，等.槲皮素对糖尿病大鼠肾脏保护主义研究[J].赣南医学院学报, 2023, 43(3): 262-6.
19	Hu TY, Yue JL, Tang QW, et al. The effect of quercetin on diabetic nephropathy (DN): a systematic review and meta-analysis of animal studies[J]. Food Funct, 2022, 13(9): 4789-803.
20	Furman BL. Streptozotocin-induced diabetic models in mice and rats[J]. Curr Protoc Pharmacol, 2015, 70: 5.47.1-5.47.20.
21	茅莉娜, 王凤岩, 周轶琳,等.糖尿病肾病大鼠模型的制备[J].中文科技期刊数据库(全文版)医药卫生, 2023, 9: 11-4.
22	张书力, 冯丹.槲皮素通过下调缓激肽受体B1表达减轻糖尿病大鼠神经病理性疼痛[J].中国免疫学杂志, 2024, 40(2): 337-42.
23	张煜敏，张桢烨，钱玲玲，等. 槲皮素通过AKT/FOXO3信号通路保护糖尿病大鼠心肌细胞[J]. 江苏大学学报(医学版), 2021, 31(3):185-9.
24	Maksymchuk O, Shysh A, Rosohatska I, et al. Quercetin prevents type 1 diabetic liver damage through inhibition of CYP2E1[J]. Pharmacol Rep, 2017, 69(6): 1386-92.
25	Tang LX, Li K, Zhang Y, et al. Quercetin liposomes ameliorate streptozotocin-induced diabetic nephropathy in diabetic rats[J]. Sci Rep, 2020, 10(1): 2440.
26	王兴红，邓海峰，孙缦利. 槲皮素对糖尿病大鼠肾脏GSK3β信号通路的影响[J].中阿科技论坛(中英文), 2021, 9: 73-5.
27	Lontchi-Yimagou E, Sobngwi E, Matsha TE, et al. Diabetes mellitus and inflammation[J]. Curr Diab Rep, 2013, 13(3): 435-44.
28	Mora C, Navarro JF. Inflammation and diabetic nephropathy[J]. Curr Diab Rep, 2006, 6(6): 463-8.
29	Volz HC, Seidel C, Laohachewin D, et al. HMGB1: the missing link between diabetes mellitus and heart failure[J]. Basic Res Cardiol, 2010, 105(6): 805-20.
30	Chen XC, Ma J, Kwan T, et al. Blockade of HMGB1 attenuates diabetic nephropathy in mice[J]. Sci Rep, 2018, 8(1): 8319.
31	Markó L, Vigolo E, Hinze C, et al. Tubular epithelial NF-κB activity regulates ischemic AKI[J]. J Am Soc Nephrol, 2016, 27(9): 2658-69.
32	Bönner F, Gastl M, Nienhaus F, et al. Regional analysis of inflammation and contractile function in reperfused acute myocardial infarction by in vivo ¹⁹F cardiovascular magnetic resonance in pigs[J]. Basic Res Cardiol, 2022, 117(1): 21.

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槲皮素通过抑制HMGB1/RAGE/NF-κB信号通路减轻糖尿病引起的大鼠肾脏损伤

Quercetin ameliorates diabetic kidney injury in rats by inhibiting the HMGB1/RAGE/ NF-κB signaling pathway

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