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大黄-丹参药对对慢性肾衰竭模型大鼠肠源性尿毒素含量和肠道屏障功能的影响
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篇名: 大黄-丹参药对对慢性肾衰竭模型大鼠肠源性尿毒素含量和肠道屏障功能的影响
TITLE: Effects of Couplet Medicine of Rheum palmatum -Salvia miltiorrhiza on Enterogenous Urotoxins Contents and Intestinal Barrier Function in Rats with Chronic Renal Failure
摘要: 目的:研究大黄-丹参药对对慢性肾衰竭(CRF)模型大鼠肠源性尿毒素含量和肠道屏障功能的影响。方法:将55只雄性Wistar大鼠随机分为假手术组(10只)和造模组(45只),假手术组大鼠分离肾组织但不切除,造模组大鼠采用5/6肾切除法复制CRF模型。造模成功后(剔除死亡和不成模大鼠5只),将模型大鼠分为模型组(水)、尿毒清颗粒组(2.5g/kg)和大黄-丹参药对高、低剂量组(6、3g/kg,以生药量计),每组10只。假手术组和模型组大鼠灌胃等体积水,各给药组灌胃相应药物,每天1次,连续12周。末次给药后,采用全自动生化分析仪检测各组大鼠血清中肌酐(Scr)、尿素氮(BUN)含量和24h尿液中尿肌酐(Ucr)含量,并计算肌酐清除率(Ccr);采用超高效液相色谱-电喷雾串联三重四极杆质谱法同时测定大鼠血清中尿毒素[氧化三甲胺(TMAO)、硫酸吲哚酚(IS)、硫酸对甲酚(PCS)]的含量;采用实时荧光定量聚合酶链式反应(RT-PCR)法、免疫荧光法分别检测大鼠回肠组织中闭合蛋白(Occludin)、紧密连接蛋白1(ZO-1)的mRNA和蛋白表达水平;采用苏木素-伊红染色法、Masson染色法观察大鼠肾组织的病理学变化;采用透射电镜法观察大鼠结肠组织的超微结构变化。结果:与假手术组比较,模型组大鼠血清中Scr、BUN、TMAO、PCS、IS含量均显著升高(P<0.01),尿液中Ucr含量和Ccr及回肠组织中Occludin、ZO-1的mRNA及蛋白表达水平均显著降低(P<0.01);肾组织中肾小球硬化、肾小管扩张,肾间质可见炎性细胞浸润和纤维化;结肠上皮屏障结构重度损伤。与模型组比较,各给药组大鼠血清中Scr、BUN、TMAO、PCS、IS含量均显著降低(P<0.05或P<0.01);尿液中Ucr含量和回肠组织中Occlu-din、ZO-1的mRNA及蛋白表达水平均显著升高(大黄-丹参药对低剂量组的ZO-1mRNA除外,P<0.05或P<0.01);肾间质炎性细胞浸润、纤维化程度和结肠上皮屏障结构损伤程度均减轻。结论:大黄-丹参药对能有效保护CRF模型大鼠残存的肾功能,其作用机制可能与降低大鼠血清中肠源性尿毒素含量,上调回肠组织中Occludin、ZO-1的mRNA及蛋白表达水平从而改善肠道屏障功能有关。
ABSTRACT: OBJECTIVE:To study the effects of couplet medicine of Rheum p almatum-Salvia miltiorrhiza on the contents of enterogenous urotoxin and intestinal barrier function in chronic renal failure (CRF)model rats. METHODS :Totally 55 male Wistar rats were randomly divided into sham operation group (10 rats)and modeling group (45 rats). In sham operation group ,the kidneys were isolated but not removed ;CRF model was reproduced by 5/6 nephrectomy in modeling group. After modeling (excluding 5 dead and non-modeling rats ),modeling rats were divided into model group (water),Niaoduqing granules group (2.5 g/kg),couplet medicine of R. palmatum -S. miltiorrhiza groups(6,3 g/kg,by crude drug ),with 10 rats in each group. Sham operation group and model group were given constant volume of water intragastrically. Administration groups were given relevant medicine intragastrically ,once a day ,for consecutive 12 weeks. After last administration ,the contents of creatinine (Scr)and urea nitrogen(BUN)in serum ,the content of urinary creatinine (Ucr) in urine were determined by automatic biochemical analyzer;creatinine clearance rate (Ccr)was calculated. The contents of enterogenous urotoxin [trimethylamine-N-oxide (TMAO),indoxyl sulfate (IS)and p-cresyl sulphate (PCS)] were determined by UPLC-ESI-MS/MS. Real-time RT-PCR and immunofluorescence assay were used to detect the mRNA and protein expression of Occludin and ZO-1 in the ileum tissue. HE staining and Masson staining were used to observe the pathologi cal changes of renal tissue. The ultrastructural changes of rat colon were observed by transmission electron microscope. RESULTS :Compared with sham operation group ,serum contents of Scr,BUN,TMAO,PCS and IS were increased significantly in model group (P<0.01),while urine content of Ucr ,Ccr,mRNA and protein expression of Occludin and ZO- 1 in ileum tissue were decreased significantly (P<0.01);renal glomerulosclerosis , renal tubules dilation and inflammatory invasion and fibrosisin the interstitium were all found ;the intestinal epithelial barrier structure of colon tissue was severely damaged. Compared with model group ,serum contents of Scr ,BUN,TMAO,PCS and IS were decreased significantly in administration groups (P<0.05 or P<0.01);the mRNA and protein expression of Occludin and ZO-1 in the ileum tissue were increased significantly (except for mRNA expression of ZO- 1 in R. palmatum -S. miltiorrhiza low-dose group (P<0.05 or P<0.01);the infiltration of inflammatory cells in renal interstitium ,the degree of fibrosis and the damage of intestinal epithelial barrier structure in colon tissue were reduced. CONCLUSIONS :Couplet medicine of R. palmatum -S. miltiorrhiza can effectively protect the residual renal function of CRF model rats ,the mechanism of which may be associated with reducing the serum contents of enterogenous urotoxin ,up-regulating mRNA and protein expresssion of Occludin and ZO- 1 in the ileum tissue so as to improve intestinal barrier function.
期刊: 2021年第32卷第07期
编辑: 王宏,徐娟,江茜,康利,刘伟伟,袁玲,崔晓雪,刘琳娜,冯仁蕊,王蕾,李燕林
AUTHORS: WANG Hong,XU Juan,JIANG Qian,KANG Li,LIU Weiwei,YUAN Ling,CUI Xiaoxue,LIU Linna,FENG Renrui,WANG Lei,LI Yanlin
关键字: 大黄;丹参;慢性肾衰竭;肠源性尿毒素;肠道屏障;大鼠
KEYWORDS: Rheum palmatum ;Salvia miltiorrhiza ;Chronic renal failure ;Enterogenous urotoxins ;Intestinal barrier ;Rats
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