缬沙坦联合霉酚酸酯对糖尿病大鼠肾脏TRAIL及NF-κB的影响
힐사탄연합매분산지대당뇨병대서신장TRAIL급NF-κB적영향
Effects of valsartan, mycophenolate mofetil and their combined application on TRAIL and nuclear factor-κB expression in the kidneys of diabetic rats
  • 万方数据
    中华医学杂志 중화의학잡지
    National Medical Journal of China
    2008年 8期 540-545 ,共6页

    陈兵%张燕%柳刚%关广聚%侯香华%李学刚%刘军莉

    진병%장연%류강%관엄취%후향화%리학강%류군리

    霉酚酸%糖尿病肾病%NF-κB%肿瘤坏死因子 黴酚痠%糖尿病腎病%NF-κB%腫瘤壞死因子
    매분산%당뇨병신병%NF-κB%종류배사인자
    Mycophenolic acid%Diabetic nephropathies%NF-kappa B%Tumor necrosis factor
    目的 探讨肿瘤坏死因子相关的凋亡诱导配体(TRAIL)及其核因子-κB(NF-κB)在糖尿病大鼠肾组织的表达及其联合应用缬沙坦(valsartan)和霉酚酸酯(MMF)对糖尿病大鼠肾组织TRAIL及其NF-κB的影响.方法 采用一侧肾切除腹腔注射STZ(55 mg/kg)建立糖尿病大鼠模型,将80只Wistar大鼠随机分为:对照组(NC)、糖尿病组(DM)、缬沙坦治疗组(DM+V)、霉酚酸酯治疗组(DM+M)、联合治疗组(DM+V+M).取材,检测各项生化指标,并采用荧光实时定量RQ-PCR方法检测肾皮质TRAIL及其NF-κB的mRNA的表达.免疫组织化学测定肾组织TRAIL及其NF-κB蛋白的表达.结果 ①DM组24 h尿蛋白和肾重/体重比均高于NC组(均P＜0.05),并随糖尿病时程延长逐渐增高,于DM12周时达到最大值;血白蛋白在DM8周组开始下降(P＜0.01),并逐渐降低;血肌酐、尿素氮于DM16周组开始下降(P＜0.01).各治疗组与DM8周组相比较,肾重/体重比变小(P＜0.05),24 h尿蛋白总量降低(均P＜0.05),血白蛋白回升(P＜0.05).以联合组最为明显.②荧光定量PCR显示TRAIL在12周前表达降低(均P＜0.01),16周时其表达量明显升高(P＜0.01).各治疗组与DM8周组比较表达增加(P＜0.05),以霉酚酸酯组和联合组最为明显(P＜0.01).DM组NF-κB的mRNA表达随时间延长逐渐增强(P＜0.01),各治疗组与DM8周组比较表达均降低(均P＜0.05),以联合组最为明显.③免疫组化显示TRAIL主要在肾曲小管表达,肾小球和脉管系统没有表达.DM各组在12周前表达均降低(均P＜0.05),差异有统计学意义;16周后表达明显增强(均P＜0.01).各治疗组阳性细胞数明显增加(均P＜0.05).NF-κB在肾小球和肾小管均有表达,DM各组NF-κB表达量随时间逐渐增高,各治疗组可显著降低NF-κB表达.结论 TRAIL作为自身免疫系统的一个重要监控因子,其在糖尿病大鼠肾脏中的表达说明其密切参与了糖尿病肾病的发生发展,机制可能由NF-κB调节.早期缬沙坦和霉酚酸酯联合干预治疗可通过来增强TRAIL的表达,对肾脏产生保护作用.
    목적 탐토종류배사인자상관적조망유도배체(TRAIL)급기핵인자-κB(NF-κB)재당뇨병대서신조직적표체급기연합응용힐사탄(valsartan)화매분산지(MMF)대당뇨병대서신조직TRAIL급기NF-κB적영향.방법 채용일측신절제복강주사STZ(55 mg/kg)건립당뇨병대서모형,장80지Wistar대서수궤분위:대조조(NC)、당뇨병조(DM)、힐사탄치료조(DM+V)、매분산지치료조(DM+M)、연합치료조(DM+V+M).취재,검측각항생화지표,병채용형광실시정량RQ-PCR방법검측신피질TRAIL급기NF-κB적mRNA적표체.면역조직화학측정신조직TRAIL급기NF-κB단백적표체.결과 ①DM조24 h뇨단백화신중/체중비균고우NC조(균P＜0.05),병수당뇨병시정연장축점증고,우DM12주시체도최대치;혈백단백재DM8주조개시하강(P＜0.01),병축점강저;혈기항、뇨소담우DM16주조개시하강(P＜0.01).각치료조여DM8주조상비교,신중/체중비변소(P＜0.05),24 h뇨단백총량강저(균P＜0.05),혈백단백회승(P＜0.05).이연합조최위명현.②형광정량PCR현시TRAIL재12주전표체강저(균P＜0.01),16주시기표체량명현승고(P＜0.01).각치료조여DM8주조비교표체증가(P＜0.05),이매분산지조화연합조최위명현(P＜0.01).DM조NF-κB적mRNA표체수시간연장축점증강(P＜0.01),각치료조여DM8주조비교표체균강저(균P＜0.05),이연합조최위명현.③면역조화현시TRAIL주요재신곡소관표체,신소구화맥관계통몰유표체.DM각조재12주전표체균강저(균P＜0.05),차이유통계학의의;16주후표체명현증강(균P＜0.01).각치료조양성세포수명현증가(균P＜0.05).NF-κB재신소구화신소관균유표체,DM각조NF-κB표체량수시간축점증고,각치료조가현저강저NF-κB표체.결론 TRAIL작위자신면역계통적일개중요감공인자,기재당뇨병대서신장중적표체설명기밀절삼여료당뇨병신병적발생발전,궤제가능유NF-κB조절.조기힐사탄화매분산지연합간예치료가통과래증강TRAIL적표체,대신장산생보호작용.
    Objective To evaluate the expression of TNF-related apoptosis inducing ligand (TRAIL) and nuclear factor (NF)-κB in the kidney tissues of diabetic rats and the effects of valsartan,mycophenolate mofetil (MMF),and their combined application on the renal TRAIL and NF-κB expression.Methods Eighty uninephrectomized male Wistar rats were randomly divided into 2 groups:normal control (NC) group (n=28),undergoing intraperitoneal injection of citric acid buffer,and diabetes mellitus (DM) group,undergoing intraperitoneal injection of streptozotocin (STZ) to establish DM models.The 52 DM rats were randomly divided into 7 equal subgroups:DM without treatment for 4 weeks (DM4),DM without treatment for 8 weeks (DM8) DM without treatment for 12 weeks (DM12),and DM without treatment for 16 weeks (DM16),valsartan treatment (DM+V),MMF treatment (DM+M),and combined treatment (DM+V+M).The treatment subgroups were treated for 8 weeks immediately after the diabetic models ere established.Twenty-four hour urine was collected to measure the amount of protein 4,8,12,and 16 weeks after the induction of DM respectively.The rats were sacrificed.Blood samples were collected from the abdominal aorta to detect the blood urea nitrogen (BUN),serum creatinine (sCr),albumin,and glucose.The kidneys were taken out.Hypertrophy index (left kidney weight/body weight) was determined.Quantitative real time RT-PCR was performed to detect the expression of TRAIL and NF-κB The 24 h urine protein levels and hypertrophy indexes of all DM subgroups were significantly higher than those of the NC groups (all P＜0.05).24 h urine protein and hypertrophy index increased gradually and peaked in the12th week;blood albumin gradually decreased since the 8th week (P＜0.01),and BUN and sCr began to decrease only since the 16th week (both P＜0.01).Compared with the DM 8 subgroup,the hypertrophy index and 24 h urine protein of the different treatment subgroups,especially the DM+V+M with the NC group,the TRAIL expression levels of the DM subgroups were significantly lower before the 12th week after induction of DM model (all P＜0.01),and then significantly highet in the 16th week (all P＜0.01).The TRAIL expression of the treatment groups,especially that of the DM+M subgroup,were significantly higher than that of the DM8 group (all P＜0.05).Compared with the NC group,the NF-κB expression levels of the DM subgroups were significantly higher time-dependently (all P＜0.01).Compared with the DM8 group,the NF-κB expression levels of the treatment subgroups,especially that of the DM+Vthe convoluted tubtde of kidney,and no TRAIL protein expression was detected in the glomeruli or renal vasculature.The levels of NF-κB protein expression,shown in glomeruli and convoluted tubules,of all DM subgroups were all higher than that of the NC group.The NF-κB protein expression level of the DM+V+M subgroup was significantly lower.The number of NF-κB positive cells was significantly related to the mononuclear macrophage infiltration,kidney function,and structural lesion.Conclusion An important monitoring factor in the autoimmune system,TRAIL closely participates in the pathogenesis of diabetic nephropathy,possibly controlled by NF-κB.In the early stage combination of valsartan and MMF may up-regulate the expression of TRAIL,thus protecting the kidney function.
    원문보기 원문다운로드 사이트로이동
저자의 최근 논문