基于HMGB1/TLR4信号通路评价五味子乙素对2型糖尿病肾病大鼠肾脏功能的保护作用
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摘要
目的研究五味子乙素(Sch B)对2型糖尿病肾病(DN)大鼠肾脏功能的保护作用及其对HMGB1/TLR4炎性通路的影响。方法 40只SD大鼠随机分为正常对照组、DN组、DN低剂量Sch B组及DN高剂量Sch B组,采用尾静脉注射链脲佐菌素构建DN模型,并同时给予药物治疗。治疗4周后处死大鼠取材,检测谷丙转氨酶(ALT)、尿肌酐(Ucr)、血肌酐(Scr)、血胱抑素C(Cys-c)及内生肌酐清除率(Ccr); HE染色观察大鼠肾脏组织结构变化; Western blot法分析肾脏组织HMGB1、TLR4、IL-1β、IL-6及TNF-α蛋白表达量。结果与正常对照组比较,DN组大鼠Scr、Cys-c及ALT水平显著升高,Ucr、Ccr水平则显著降低(P <0. 05),肾脏组织形态明显异常,并且HMGB1、TLR4、IL-1β、IL-6及TNF-α蛋白表达量均显著升高(P <0. 05);与DN组大鼠比较,经低、高剂量Sch B治疗后大鼠Scr、Cys-c及ALT水平明显降低,Ucr、Ccr水平则显著升高(P <0. 05),并且HMGB1、TLR4、IL-1β、IL-6及TNF-α蛋白表达量均显著降低(P <0. 05)。结论 Sch B可改善DN大鼠肾脏功能,其机制可能与降低HMGB1/TLR4信号蛋白表达、发挥抗炎作用有关。
Objective To study the protective effects of Schisandrin B( Sch B) on renal function in rates with type 2 diabetic nephropathy,and investigate the influence of Schisandrin B on HMGB1/TLR4 inflammatory pathway. Methods 40 SD rats were randomly divided into normal control group,diabetic nephropathy( DN) group,DN low-dose of Sch B group and DN high-dose of Sch B group.The DN model was constructed through the tail vein injection of streptozotocin. The rats in each group were sacrificed after treatment for 4 weeks. The levels of alanine transaminase( ALT),urinary creatinine( Ucr),serum creatinine( Scr),blood cystatin C( Cys-C),and creatinine clearance rate( Ccr) were determined. HE staining was used to observe the histological changes of renal tissues. Western blot were used to detect the expressions of HMGB1,TLR4,IL-1β,IL-6 and TNF-α. Results Compared with control group,the levels of Scr,Cys-c and ALT were gratly increased,while the levels of Ucr and Ccr significnatly decreased in DN group( P < 0. 05). The kidney tissue morphology in DN rats was abnormal. The expression levels of HMGB1,TLR4,IL-1β,IL-6 and TNF-α in DN group were significantly increased compared with control group( P < 0. 05). However,after treatment with low-and high-dose Sch B,the levels of Scr,Cys-c and ALT were gratly decreased,while the levels of Ucr and Ccr significnatly increased in Sch B groups( P < 0. 05). The expression levels of HMGB1,TLR4,IL-1β,IL-6 and TNF-α in Sch B groups were significantly decreased compared with DN group( P < 0. 05). Conclusion Sch B can improve the kidney function of diabetic rats,and its mechanism may be related to the down-regulation of HMGB1/TR4 signaling protein expressions,which plays the anti-inflammatory effects.
Objective To study the protective effects of Schisandrin B( Sch B) on renal function in rates with type 2 diabetic nephropathy,and investigate the influence of Schisandrin B on HMGB1/TLR4 inflammatory pathway. Methods 40 SD rats were randomly divided into normal control group,diabetic nephropathy( DN) group,DN low-dose of Sch B group and DN high-dose of Sch B group.The DN model was constructed through the tail vein injection of streptozotocin. The rats in each group were sacrificed after treatment for 4 weeks. The levels of alanine transaminase( ALT),urinary creatinine( Ucr),serum creatinine( Scr),blood cystatin C( Cys-C),and creatinine clearance rate( Ccr) were determined. HE staining was used to observe the histological changes of renal tissues. Western blot were used to detect the expressions of HMGB1,TLR4,IL-1β,IL-6 and TNF-α. Results Compared with control group,the levels of Scr,Cys-c and ALT were gratly increased,while the levels of Ucr and Ccr significnatly decreased in DN group( P < 0. 05). The kidney tissue morphology in DN rats was abnormal. The expression levels of HMGB1,TLR4,IL-1β,IL-6 and TNF-α in DN group were significantly increased compared with control group( P < 0. 05). However,after treatment with low-and high-dose Sch B,the levels of Scr,Cys-c and ALT were gratly decreased,while the levels of Ucr and Ccr significnatly increased in Sch B groups( P < 0. 05). The expression levels of HMGB1,TLR4,IL-1β,IL-6 and TNF-α in Sch B groups were significantly decreased compared with DN group( P < 0. 05). Conclusion Sch B can improve the kidney function of diabetic rats,and its mechanism may be related to the down-regulation of HMGB1/TR4 signaling protein expressions,which plays the anti-inflammatory effects.
引文
1 Sidaway P. Diabetic nephropathy:Heparanase mediates renal injury[J]. Nat Rev Nephrol,2014,10(9):483-489
2 Ni WJ,Tang LQ,Wei W. Research progress in signalling pathway in diabetic nephropathy[J]. Diabetes Metab Res Rev,2018,31(3):221-233
3 汪建云,王栋栋,陆昭磊,等.四氢生物蝶呤在2型糖尿病肾病小鼠肾脏NO生成中的作用[J].中国药理学通报,2014,30(4):514-519
4 Chi W,Chen H,Li F,et al. HMGB1 promotes the activation of NLRP3 and caspase-8 inflammasomes via NF-κB pathway in acute glaucoma[J]. J Neuroinflammation,2015,12(5):137-145
5 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
6 Lee TH,Jung CH,Lee DH. Neuroprotective effects of Schisandrin B against transient focal cerebral ischemia in Sprague-Dawley rats[J].Food Chem Toxicol,2017,50(12):4239-4245
7 Leong PK,Ko KM. Schisandrin B induces an Nrf2-mediated thioredoxin expression and suppresses the activation of inflammasome in vitro and in vivo[J]. Biofactors,2015,41(5):314-323
8 Thandavarayan RA,Giridharan VV,Arumugam S,et al. Schisandrin B prevents doxorubicin induced cardiac dysfunction by modulation of DNA damage,oxidative stress and inflammation through inhibition of MAPK/p53 signaling[J]. PLo S One,2015,10(3):e0119214
9 Cao YP,Liu QJ,Ren YZ,et al. Losartan provides protection on the kidney of diabetic rats by inhibiting the expression of GADDl53/CHOP[J]. Chin Pharmacol Bull,2011,27(5):617-622
10 Tang LQ,Liu S,Zhang ST,et al. Berberine regulates the expression of E-prostanoid receptors in diabetic rats with nephropathy[J]. Mol Biol Rep,2016,41(5):3339-3347
11 郑海洲,张杰,肖程程,等.五味子乙素抗肾纤维化作用及机制研究[J].中国现代医学杂,2017,27(27):1-6
12 原丽欣.五味子乙素对顺铂所致大鼠肾氧化损伤的保护作用[J].中国医院药学杂志,2014,31(10):825-828
13 张巍,于为民,任小军.糖尿病肾病的炎症反应张[J].中国现代医生,2014,52(9):157-160
14 B rgeson E,Johnson AM,Lee YS,et al. Lipoxin A4 attenuates obesity-induced adipose inflammation and associated liver and kidney disease[J]. Cell Metab,2015,22(1):125-137
15 Dasu MR,Jialal I. Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors[J]. Am J Physiol Endocrinol Metab,2017,14(3):e145-e154
16 Liu W,Wu YH,Zhang L,et al. MicroRNA-146a suppresses rheumatoid arthritis fibroblast-like synoviocytes proliferation and inflammatory responses by inhibiting the TLR4/NF-κB signaling[J]. Oncotarget,2018,9(35):23944-23959
17 Antón M,Alén F,Gómez de Heras R,Serrano A,et al. Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF-κB danger signaling in rat frontal cortex and depressive-like behavior induced by ethanol binge administration[J]. Addict Biol,2017,22(3):724-741
18 Xu J,Lu C,Liu Z,et al. Schizandrin B protects LPS-induced sepsis via TLR4/NF-κB/My D88 signaling pathway[J]. Am J Transl Res,2018,10(4):1155-1163
2 Ni WJ,Tang LQ,Wei W. Research progress in signalling pathway in diabetic nephropathy[J]. Diabetes Metab Res Rev,2018,31(3):221-233
3 汪建云,王栋栋,陆昭磊,等.四氢生物蝶呤在2型糖尿病肾病小鼠肾脏NO生成中的作用[J].中国药理学通报,2014,30(4):514-519
4 Chi W,Chen H,Li F,et al. HMGB1 promotes the activation of NLRP3 and caspase-8 inflammasomes via NF-κB pathway in acute glaucoma[J]. J Neuroinflammation,2015,12(5):137-145
5 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
6 Lee TH,Jung CH,Lee DH. Neuroprotective effects of Schisandrin B against transient focal cerebral ischemia in Sprague-Dawley rats[J].Food Chem Toxicol,2017,50(12):4239-4245
7 Leong PK,Ko KM. Schisandrin B induces an Nrf2-mediated thioredoxin expression and suppresses the activation of inflammasome in vitro and in vivo[J]. Biofactors,2015,41(5):314-323
8 Thandavarayan RA,Giridharan VV,Arumugam S,et al. Schisandrin B prevents doxorubicin induced cardiac dysfunction by modulation of DNA damage,oxidative stress and inflammation through inhibition of MAPK/p53 signaling[J]. PLo S One,2015,10(3):e0119214
9 Cao YP,Liu QJ,Ren YZ,et al. Losartan provides protection on the kidney of diabetic rats by inhibiting the expression of GADDl53/CHOP[J]. Chin Pharmacol Bull,2011,27(5):617-622
10 Tang LQ,Liu S,Zhang ST,et al. Berberine regulates the expression of E-prostanoid receptors in diabetic rats with nephropathy[J]. Mol Biol Rep,2016,41(5):3339-3347
11 郑海洲,张杰,肖程程,等.五味子乙素抗肾纤维化作用及机制研究[J].中国现代医学杂,2017,27(27):1-6
12 原丽欣.五味子乙素对顺铂所致大鼠肾氧化损伤的保护作用[J].中国医院药学杂志,2014,31(10):825-828
13 张巍,于为民,任小军.糖尿病肾病的炎症反应张[J].中国现代医生,2014,52(9):157-160
14 B rgeson E,Johnson AM,Lee YS,et al. Lipoxin A4 attenuates obesity-induced adipose inflammation and associated liver and kidney disease[J]. Cell Metab,2015,22(1):125-137
15 Dasu MR,Jialal I. Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors[J]. Am J Physiol Endocrinol Metab,2017,14(3):e145-e154
16 Liu W,Wu YH,Zhang L,et al. MicroRNA-146a suppresses rheumatoid arthritis fibroblast-like synoviocytes proliferation and inflammatory responses by inhibiting the TLR4/NF-κB signaling[J]. Oncotarget,2018,9(35):23944-23959
17 Antón M,Alén F,Gómez de Heras R,Serrano A,et al. Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF-κB danger signaling in rat frontal cortex and depressive-like behavior induced by ethanol binge administration[J]. Addict Biol,2017,22(3):724-741
18 Xu J,Lu C,Liu Z,et al. Schizandrin B protects LPS-induced sepsis via TLR4/NF-κB/My D88 signaling pathway[J]. Am J Transl Res,2018,10(4):1155-1163