[1]李硕,倪向敏,徐喆,等.雌马酚对2型糖尿病大鼠的肾脏保护作用[J].陆军军医大学学报(原第三军医大学学报),2022,44(10):1009-1017.
 LI Shuo,NI Xiangmin,XU Zhe,et al.Renal protective effect of equol on type 2 diabetic rats [J].J Amry Med Univ (J Third Mil Med Univ),2022,44(10):1009-1017.
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雌马酚对2型糖尿病大鼠的肾脏保护作用(/HTML )
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陆军军医大学学报(原第三军医大学学报)[ISSN:1000-5404/CN:51-1095/R]

卷:
44卷
期数:
2022年第10期
页码:
1009-1017
栏目:
基础医学
出版日期:
2022-05-30

文章信息/Info

Title:
Renal protective effect of equol on type 2 diabetic rats 
 
作者:
李硕倪向敏徐喆张贵明崔涵强王建
陆军军医大学(第三军医大学)第二附属医院营养科 
Author(s):
LI Shuo NI Xiangmin XU Zhe ZHANG Guiming CUI Hanqiang WANG Jian

Department of Nutrition, Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, China

关键词:
雌马酚2型糖尿病肾脏氧化应激炎症反应核因子E2相关因子2
Keywords:
 
分类号:
R282.71; R587.1; R692
文献标志码:
A
摘要:

目的探讨雌马酚(equol,Eq)对2型糖尿病(type 2 diabetes mellitus,T2DM)大鼠的肾脏保护效应和对肾组织氧化应激、炎症因子水平的影响及其可能作用机制。方法选取6周龄SD大鼠50只,对照组(n=10)给予普通饲料喂养;40只高脂高糖饮食联合链脲佐菌素腹腔注射建立T2DM大鼠模型,建模成功34只,T2DM模型组(n=9)给予高脂高糖饲料喂养,Eq干预组在模型组基础上分别给予低剂量(EqL,20 mg·kg-1·d-1,n=9)、中剂量(EqM,40 mg·kg-1·d-1,n=8)、高剂量(EqH,80 mg·kg-1·d-1,n=8)Eq灌胃干预。连续干预12周后,检测大鼠血清肌酐(creatinine,CREA)、尿素氮(blood urea nitrogen, BUN)、尿酸(uric acid,UA)及肾组织氧化应激、炎症因子指标水平,HE、PAS染色显示肾组织显微结构变化,Western blot及RT-PCR检测肾组织核因子E2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)/血红素氧合酶-1(heme oxygenase 1,HO-1)通路激活/抑制情况。结果干预12周后,与对照组相比,模型组T2DM大鼠血清CREA、BUN、UA水平显著升高(P<0.05),肾组织丙二醛(malondialdehyde,MDA)、TNF-α等氧化应激及炎症指标水平显著升高(P<0.05),HE、PAS染色结果显示肾小球体积增大、系膜基质增多,肾小囊基底膜增厚,肾小管萎缩、管腔扩张,肾组织总Nrf2、HO-1蛋白和mRNA表达水平及核Nrf2蛋白水平显著降低(P<0.05);与模型组相比,各Eq干预组血清CREA、BUN、UA水平显著降低(P<0.05),肾组织MDA、TNF-α等氧化应激及炎症指标水平显著降低(P<0.05),HE、PAS染色结果显示肾显微结构损伤明显减轻,总Nrf2、HO-1 蛋白和mRNA表达水平及核Nrf2蛋白水平显著升高(P<0.05),各Eq干预组组间相比差异无统计学意义。结论雌马酚能够降低T2DM大鼠肾脏组织氧化应激和炎症因子水平,发挥肾脏保护效应,Nrf2/HO-1通路可能在其中发挥重要作用。

Abstract:
ObjectiveTo investigate the effect of equol (Eq) on oxidative stress and inflammatory factors in renal tissue in type 2 diabetes mellitus (T2DM) rats, and explore the possible mechanism in the process.  MethodsFifty SD rats aged 6 weeks were selected, and 40 of them were given high-fat and high-sugar diet combined with intraperitoneal injection of streptozotocin to establish T2DM rat model, and finally 34 out of 40 were successfully modeled. The rats from the control group (n=10) was fed with ordinary diet, and the T2DM rats were further divided into model group (n=9), and low- (n=9), medium- (n=8) and high-dose (n=8) Eq intervention groups (gavage intervention of 20, 40 and 80 mg/kg Eq, respectively). After 12 consecutive weeks of intervention, serum creatinine (CREA), blood urea nitrogen (BUN), uric acid (UA), and levels of renal oxidative stress and inflammatory factors were detected in each group of rats. HE and PAS stainings were adopted to reveal the histological changes of renal tissue. Western blotting and RT-PCR were performed to determine the activation or inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway in renal tissue. ResultsAs compared with the control group, the serum levels of CREA, BUN and UA were significantly increased in the T2DM model group (P<0.05), and the levels of oxidative stress and inflammation indicators such as malondialdehyde (MDA) and TNF-α in renal tissue were remarkably elevated as well (P<0.05). The results of HE and PAS stainings showed increased glomerular volume and mesangial matrix, thickened basement membrane of renal capsule, atrophy of renal tubules and dilation of lumen in the model group. Moreover, the protein and mRNA levels of total Nrf2 and HO-1, as well as the expression of nuclear Nrf2 protein were all greatly reduced (P<0.05). In comparison with the model group, the serum levels of CREA, BUN and UA in the 3 Eq intervention groups were significantly decreased (P<0.05), levels of oxidative stress and inflammation indexes in renal tissue were reduced (P<0.05), and the damage of renal microstructure was notably improved. In addition, the protein and mRNA expression of total Nrf2 and HO-1, and nuclear Nrf2 protein level were obviously enhanced (P<0.05). There was no statistical difference among Eq intervention groups. ConclusionEq reduces the levels of oxidative stress and inflammatory factors in the renal tissue of T2DM rats, exerting a protective effect on the kidney, in which Nrf2/HO-1 pathway may play an important role. 
 

参考文献/References:

[1]KHAN R M M, CHUA Z J Y, TAN J C, et al. From pre-diabetes to diabetes: diagnosis, treatments and translational research[J]. Medicina (Kaunas), 2019, 55(9): 546. DOI: 10.3390/medicina55090546. 
 
[2]Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group.KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease[J]. Kidney Int, 2020, 98(4S): S1-S115. DOI: 10.1016/j.kint.2020.06.019. 
 
[3]MARIC C, SANDBERG K, HINOJOSA-LABORDE C. Glomerulosclerosis and tubulointerstitial fibrosis are attenuated with 17beta-estradiol in the aging Dahl salt sensitive rat[J]. J Am Soc Nephrol, 2004, 15(6): 1546-1556. DOI: 10.1097/01.asn.0000128219.65330.ea. 
 
[4]HADJADJ S, GOURDY P, ZAOUI P, et al. Effect of raloxi-fene: a selective oestrogen receptor modulator: on kidney function in post-menopausal women with type 2 diabetes: results from a randomized, placebo-controlled pilot trial[J]. Diabet Med, 2007, 24(8): 906-910. DOI: 10.1111/j.1464-5491.2007.02165.x. 
 
[5]蔡源发, 张华明, 钮文异, 等. 雌马酚对大肠癌细胞增殖的影响[J]. 北京大学学报(医学版), 2017, 49(3): 383-387. DOI: 10.3969/j.issn.1671-167X.2017.03.003. 
 
CAI Y F, ZHANG H M, NIU W Y,et al. Effects of equol on colon cancer cell proliferation[J]. J Peking Univ Heal Sci, 2017, 49(3): 383-387. DOI: 10.3969/j.issn.1671-167X.2017.03.003. 
 
[6]ACHARJEE S, ZHOU J R, ELAJAMI T K, et al. Effect of soy nuts and equol status on blood pressure, lipids and inflammation in postmenopausal women stratified by metabolic syndrome status[J]. Metabolism, 2015, 64(2): 236-243. DOI: 10.1016/j.metabol.2014.09.005. 
 
[7]GHEIBI S, KASHFI K, GHASEMI A. A practical guide for induction of type-2 diabetes in rat: incorporating a high-fat diet and streptozotocin[J]. Biomed Pharmacother, 2017, 95: 605-613. DOI: 10.1016/j.biopha.2017.08.098. 
 
[8]SEKIKAWA A, IHARA M, LOPEZ O, et al. Effect of S-equol and soy isoflavones on heart and brain[J]. Curr Cardiol Rev, 2019, 15(2): 114-135. DOI: 10.2174/1573403X15666181205104717. 
 
[9]HOD R, MANIAM S, MOHD NOR N H. A systematic review of the effects of equol (soy metabolite) on breast cancer[J]. Molecules, 2021, 26(4): 1105. DOI: 10.3390/molecules26041105. 
 
[10]SETCHELL K D, CLERICI C. Equol: history, chemistry, and formation[J]. J Nutr, 2010, 140(7): 1355S-1362S. DOI: 10.3945/jn.109.119776. 
 
[11]RAFII F. The role of colonic bacteria in the metabolism of the natural isoflavone daidzin to equol[J]. Metabolites, 2015, 5(1): 56-73. DOI: 10.3390/metabo5010056. 
 
[12]ZHANG T, LIANG X Y, SHI L Y, et al. Estrogen receptor and PI3K/Akt signaling pathway involvement in S-(-) equol-induced activation of Nrf2/ARE in endothelial cells[J]. PLoS One, 2013, 8(11): e79075. DOI: 10.1371/journal.pone.0079075. 
 
[13]KANG J S, YOON Y D, HAN M H, et al. Equol inhibits nitric oxide production and inducible nitric oxide synthase gene expression through down-regulating the activation of Akt[J]. Int Immunopharmacol, 2007, 7(4): 491-499. DOI: 10.1016/j.intimp.2006.12.004. 
 
[14]陈静, 刘丽. 常用肾功能检测指标在透析治疗效果评价上的应用价值[J]. 检验医学与临床, 2017, 14(8): 1173-1176. DOI: 10.3969/j.issn.1672-9455.2017.08.050. 
 
CHEN J, LIU L. The application value of common renal function test indexes in the evaluation of dialysis treatment effect [J]. Lab Med Clin, 2017, 14(8): 1173-1176. DOI: 10.3969/j.issn.1672-9455.2017.08.050. 
 
[15]钟娟, 陈静, 青姚, 等. 川芎嗪通过抑制PI3K/Akt/mTOR通路诱导自噬改善糖尿病肾病大鼠肾损害[J]. 天津医药, 2019, 47(4): 395-400. DOI: 10.11958/20181506. 
 
ZHONG J, CHEN J, QING Y,et al. Experimental study of ligustrazine on improving renal damage in diabetic nephropathy rats by inhibiting the PI3K/Akt/mTOR pathway and inducing autophagy[J]. Tianjin Med J, 2019, 47(4): 395-400. DOI: 10.11958/20181506. 
 
[16]张灵灵, 郭利芹, 徐可. Gli2对高糖条件下肾小管上皮细胞凋亡及ROS水平影响[J]. 中国免疫学杂志, 2018, 34(6): 830-834,839. 
 
ZHANG L L, GUO L Q, XU K. Effect of Gli2 on apoptosis and ROS level in renal tubular epithelial cells under high glucose[J]. Chin J Immunol, 2018, 34(6): 830-834,839. 
 
[17]李曾一, 王松, 高宛, 等. 下调Drp1对高糖条件下肾小管上皮细胞凋亡、氧化应激及炎症因子表达的影响[J]. 郑州大学学报(医学版), 2021, 56(4): 534-538. DOI: 10.13705/j.issn.1671-6825.2020.07.113.
 
LI Z Y, WANG S, GAO W, et al. Effects of down-regulation of Drp1 on renal tubular epithelial cell apoptosis, oxidative stress and expressions of inflammatory factors under high glucose conditions[J]. J Zhengzhou Univ Med Sci, 2021, 56(4): 534-538. DOI: 10.13705/j.issn.1671-6825.2020.07.113. 
 
[18]周建华, 李晓华, 贝鹏剑, 等. 早期2型糖尿病肾病患者血糖波动与氧化应激、炎症及单核细胞自噬的相关性[J]. 中国老年学杂志, 2021, 41(1): 32-36. DOI: 10.3969/j.issn.1005-9202.2021.01.009. 
 
ZHOU J H, LI X H, BEI P J, et al. Correlation of blood glucose fluctuation with oxidative stress, inflammation and monocyte autophagy in patients with early type 2 diabetic nephropathy [J]. Chin J Gerontol, 2021, 41(1): 32-36. DOI: 10.3969/j.issn.1005-9202.2021.01.009. 
 
[19]KINASHI H, ITO Y, SUN T, et al. Roles of the TGF-β—VEGF-C pathway in fibrosis-related lymphangiogenesis[J]. Int J Mol Sci, 2018, 19(9): 2487. DOI: 10.3390/ijms19092487. 
 
[20]SU H, LEI C T, ZHANG C. Interleukin-6 signaling pathway and its role in kidney disease: an update[J]. Front Immunol, 2017, 8: 405. DOI: 10.3389/fimmu.2017.00405. 
 
[21]朱永俊, 俞容, 李晓燕, 等. AngⅡ联合TNF-α促使肾小管上皮HK-2细胞发生程序性坏死[J]. 中国病理生理杂志, 2021, 37(6): 1084-1090. DOI: 10.3969/j.issn.1000-4718.2021.06.016. 
 
ZHU Y J, YU R, LI X Y,et al. Angiotension Ⅱ combined with TNF-α promotes necroptosis of renal tu-bular epithelial HK-2 cells[J]. Chin J Pathophysiol, 2021, 37(6): 1084-1090. DOI: 10.3969/j.issn.1000-4718.2021.06.016. 
 
[22]张昊悦, 赵蓓, 王业皇, 等. 大黄素通过调节Nrf2/HO-1和MAPKs抑制炎症和氧化应激机制研究[J]. 中国免疫学杂志, 2021, 37(9): 1063-1068. DOI: 10.3969/j.issn.1000-484X.2021.09.008.
 
ZHANG H Y, ZHAO B, WANG Y H,et al. Emodin inhibits inflammation and oxidative stress by regulating Nrf2/HO-1 and MAPKs[J]. Chin J Immunol, 2021, 37(9): 1063-1068. DOI: 10.3969/j.issn.1000-484X.2021.09.008.
 
[23]徐成. 核因子E2相关因子2信号通路与肾脏疾病[J]. 肾脏病与透析肾移植杂志, 2021, 30(2): 165-169. DOI: 10.3969/j.issn.1006-298X.2021.02.014. 
 
XU C. Role of nuclear factor erythroid 2-related factor 2 in kidney disease[J]. Chin J Nephrol Dial Transplant, 2021, 30(2): 165-169. DOI: 10.3969/j.issn.1006-298X.2021.02.014. 
 
[24]RIZZO M, ABATE N, CHANDALIA M, et al. Liraglutide reduces oxidative stress and restores heme oxygenase-1 and ghrelin levels in patients with type 2 diabetes: a prospective pilot study[J]. J Clin Endocrinol Metab, 2015, 100(2): 603-606. DOI: 10.1210/jc.2014-2291. 
 
[25]刘文, 章尹岗, 别志霞, 等. 黄芪甲苷对肥胖糖尿病大鼠肾脏氧化应激、Nrf2蛋白表达和胰岛β细胞的影响[J]. 疑难病杂志, 2019, 18(1): 67-71,109. DOI: 10.3969/j.issn.1671-6450.2019.01.016.
 
LIU W, ZHANG Y G, BIE Z X,et al. Effects of astragaloside on oxidative stress, Nrf2 protein expression and islet beta cells in obese diabetic rats[J]. Chin J Difficult Complicat Cases, 2019, 18(1): 67-71,109. DOI: 10.3969/j.issn.1671-6450.2019.01.016.

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更新日期/Last Update: 2022-05-23