银杏叶提取物对早期糖尿病肾病大鼠肾脏保护作用机制研究
摘要
目的观察银杏叶提取物对早期糖尿病肾病(DN)大鼠炎性反应表达的影响,探讨银杏叶提取物保护糖尿病肾病肾脏的部分机制。方法成年雄性Wistar大鼠随机分成对照组、糖尿病组和银杏叶提取物。采用腹腔注射链脲佐菌素的方法建立DN模型,银杏叶组灌胃银杏叶片溶液96 mg/(kg·d),并于实验12周时对动物进行处理,ELISA方法检测白细胞介素-6(IL-6)、晚期糖基化终产物(AGEs)、血浆Nod样受体蛋白-3(NLRP3)水平及免疫组织化学检测肾组织纤连蛋白和胶原Ⅳ蛋白水平的变化,并对部分肾脏标本进行肾脏肥大指数检测。结果 1)与对照组比较,模型组BUN和Cr水平均升高(P <0.05);与模型组比较,银杏叶组BUN和Cr浓度明显下降(P <0.01或P <0.05);2)与对照组相比较,模型组IL-6、AGEs、NLRP3表达水平均增高(P <0.05);与模型组比较,银杏叶组IL-6、AGEs、NLRP3表达水平均明显下降(P <0.01);3)与对照组相比较,模型组FN、CoⅣ蛋白表达水平均增高(P <0.05)。与模型组比较,银杏叶组FN、CoⅣ蛋白表达水平均明显下降(P <0.01)。结论炎性反应参与了DN的发病发展,银杏叶提取物可能通过抑制NLRP3炎症小体激活和AGEs-RAGE相互作用,对DN大鼠起到肾脏保护作用。
引文
[1]Makino H,Miyamoto Y,Sawai,et al.Altered gene expression related to glomerulogenesisand podocyte structure in early diabetic nephropathy of db/db mice and its restoration by pioglitazone[J].Diabetes,2006,(55)10:2747-2756.
[2]Wada J,Makino H.Inflammation and the pathogenesis of diabetic nephropathy[J].Clinical Science(London,England),2013,124:139-152.
[3]Lee HM,Kim JJ,Kim H,et al.Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes[J].Diabetes,2013,1(62):194-204.
[4]肖瑛,曾令萍,张莹莹,等.氧化苦参碱对糖尿病大鼠肾组织TLR4及炎症因子表达的影响[J].中国现代医学杂志,2018,5(28):11-16.
[5]Qiu YY,Tang LQ.Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy[J].Pharmacological Research,2016,10(114):251-264.
[6]Shahzad K,Bock F,Dong W,et al.Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy[J].Kidney International,2015,1(87):74-84.
[7]张素英,李瑞静.银杏叶提取物对糖尿病肾病大鼠NLRP3炎性体的影响[J].中国中医急症,2017,(26)12:2156.
[8]李瑞杰,张素英,李瑞静,等.银杏叶提取物对STZ诱导糖尿病肾病大鼠氧化应激及TNF-α表达的影响[J].河南中医,2018,38(7):1020-1023.
[9]王永胜,杨丽霞,程涛,等.糖尿病肾病的炎症致病机制与中药防治[J].中国实验方剂学杂志,2018,24(2):200-205.
[10]Douros A,Ebert N,Jakob O,et al.Estimating kidney function and use of oral antidiabetic drugs in elderly[J].Fundam Clin Pharmacol,2015,3(29):321-328.
[11]Galkina E,Ley K.Leukocyte recruitment and vascular injury in diabetic nephropathy[J].Nephrol,2006,2(17):368-377.
[12]Yang SM,Ka SM,Wu HL,et al.Thrombomodulin domain1a meliorates diabeticne phropathy inmiceviaanti-NF-kappaB/NLRP3 inflammasome‐mediated inflammation,enhancement of NRF2 antioxidant activity and inhibition of apoptosis[J].Diabetologia,2014,2(57):424-434.
[13]Wang C,Pan Y,Zhang QY,et al.Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation[J].PLoS One,2012,6(7):e38285.
[14]WANG yah,Ji huai-xue,XIAO shuhua.Effect ofgination on renal tubular epithelial cell apoptosis induced by renal is-ehenmia/reperfusion[J].Chin Pharmaeol Bull,2007,23(8):923-931.
[15]Chan pc,xiao Q,Fu PP.Ginkgo biloba leave exraet:biologi·cal,medicinal,and toxicological effects[J].Environ sci Health C Enbiron Carcinog Eeotoxieol Rev,2007,25(3):211-244.
[16]Clostre F.Gingo biloba extract(EGb761),State of knowledge in the dawn of the year 2000[J].Ann Pharm Fr,1999,57(Suppl 1):80-88.
[17]Zu Y,Wan LJ,Cui SY,et al.The mitochondrial Na(+)/Ca(2+)exchanger may reduce high glucose‐induced oxidative stress and nucleotide-binding oligomerization domain receptor 3 inflammasome activation in endothelial cells[J].Journal of Geriatric Cardiology,2015,3(12):270-278.
[18]Kumar Pasupulati A,Chitra PS,et al.Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy[J].Biomolecular Concepts,2016,12(7):293-309.
[19]Yeh WJ,Yang HY,Pai MH,et al.Long-term administration of advanced glycation end-product stimulates the activation of NLRP3 inflammasome and sparking the development of renal injury[J].The Journal of Nutritional Biochemistry,2017,1(39):68-76.
[2]Wada J,Makino H.Inflammation and the pathogenesis of diabetic nephropathy[J].Clinical Science(London,England),2013,124:139-152.
[3]Lee HM,Kim JJ,Kim H,et al.Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes[J].Diabetes,2013,1(62):194-204.
[4]肖瑛,曾令萍,张莹莹,等.氧化苦参碱对糖尿病大鼠肾组织TLR4及炎症因子表达的影响[J].中国现代医学杂志,2018,5(28):11-16.
[5]Qiu YY,Tang LQ.Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy[J].Pharmacological Research,2016,10(114):251-264.
[6]Shahzad K,Bock F,Dong W,et al.Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy[J].Kidney International,2015,1(87):74-84.
[7]张素英,李瑞静.银杏叶提取物对糖尿病肾病大鼠NLRP3炎性体的影响[J].中国中医急症,2017,(26)12:2156.
[8]李瑞杰,张素英,李瑞静,等.银杏叶提取物对STZ诱导糖尿病肾病大鼠氧化应激及TNF-α表达的影响[J].河南中医,2018,38(7):1020-1023.
[9]王永胜,杨丽霞,程涛,等.糖尿病肾病的炎症致病机制与中药防治[J].中国实验方剂学杂志,2018,24(2):200-205.
[10]Douros A,Ebert N,Jakob O,et al.Estimating kidney function and use of oral antidiabetic drugs in elderly[J].Fundam Clin Pharmacol,2015,3(29):321-328.
[11]Galkina E,Ley K.Leukocyte recruitment and vascular injury in diabetic nephropathy[J].Nephrol,2006,2(17):368-377.
[12]Yang SM,Ka SM,Wu HL,et al.Thrombomodulin domain1a meliorates diabeticne phropathy inmiceviaanti-NF-kappaB/NLRP3 inflammasome‐mediated inflammation,enhancement of NRF2 antioxidant activity and inhibition of apoptosis[J].Diabetologia,2014,2(57):424-434.
[13]Wang C,Pan Y,Zhang QY,et al.Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation[J].PLoS One,2012,6(7):e38285.
[14]WANG yah,Ji huai-xue,XIAO shuhua.Effect ofgination on renal tubular epithelial cell apoptosis induced by renal is-ehenmia/reperfusion[J].Chin Pharmaeol Bull,2007,23(8):923-931.
[15]Chan pc,xiao Q,Fu PP.Ginkgo biloba leave exraet:biologi·cal,medicinal,and toxicological effects[J].Environ sci Health C Enbiron Carcinog Eeotoxieol Rev,2007,25(3):211-244.
[16]Clostre F.Gingo biloba extract(EGb761),State of knowledge in the dawn of the year 2000[J].Ann Pharm Fr,1999,57(Suppl 1):80-88.
[17]Zu Y,Wan LJ,Cui SY,et al.The mitochondrial Na(+)/Ca(2+)exchanger may reduce high glucose‐induced oxidative stress and nucleotide-binding oligomerization domain receptor 3 inflammasome activation in endothelial cells[J].Journal of Geriatric Cardiology,2015,3(12):270-278.
[18]Kumar Pasupulati A,Chitra PS,et al.Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy[J].Biomolecular Concepts,2016,12(7):293-309.
[19]Yeh WJ,Yang HY,Pai MH,et al.Long-term administration of advanced glycation end-product stimulates the activation of NLRP3 inflammasome and sparking the development of renal injury[J].The Journal of Nutritional Biochemistry,2017,1(39):68-76.