不同时期应用氯沙坦治疗糖尿病肾病的比较研究
糖尿病肾病,,糖尿病肾病；转化生长因子；结缔组织生长因子；纤溶酶原激活物抑制剂-1；氯沙坦,1材料与方法,2结果,3讨论
【摘要】 目的 观察在微量白蛋白尿发生前后应用氯沙坦对糖尿病肾病的治疗作用及其机制。方法 单侧肾切除的STZ糖尿病大鼠，随机分为正常对照组(NC)、糖尿病肾病组(DN)、氯沙坦早期治疗组(DL1)和氯沙坦晚期治疗组(DL2)。DL1和DL2组分别于糖尿病模型建立后即刻或第9周起开始给予氯沙坦20mg/(kg·d)灌胃，疗程均为8周。第16周时，观测肾脏形态学及肾功能变化，并采用荧光实时定量RTPCR检测肾脏TGF-β1、CTGF、PAI-1等细胞因子的表达情况。结果 DN对照组大鼠尿微量白蛋白(UAER)持续上升；血肌酐(SCr)、肾脏肥大指数(KW/BW)、肾小球平均体积(MGV)、系膜面积比(FMA)以及肾脏TGF-β1、CTGF、PAI-1和FN的mRNA表达均明显升高，而肌酐清除率(CCr)已开始下降。DL1和DL2组以上指标均明显改善，但两组之间差异无显著性。结论 氯沙坦可通过下调肾脏细胞因子基因表达，起到肾脏保护作用；但在微量白蛋白尿出现之前进行干预并不比在微量白蛋白尿出现之后进行治疗的效果更好。【关键词】 糖尿病肾病；转化生长因子；结缔组织生长因子；纤溶酶原激活物抑制剂-1；氯沙坦
Comparative study on effect of losartan applied at different stage on diabetic nephropathy
LIU Gang,GUAN Guangju,ZHAO Jingjie,et al.Department of Nephrology,The Second Hospital of Shandong University,Jinan 250033,China
【Abstract】 Objective To estimate the renoproctive effect of angiotensin receptor antagonists on DN by applying losartan before or after microalbuminuria.Methods 40 uninephrectomized male Wistar rats are randomatically divided into 4 groups:normal control (NC),diabetic nephropathy control (DN),Losartan early treatment group (DL1) and Losartan late treatment group (DL2).Rats were made diabetic by single intraperitoneal injection of streptozotocin (STZ,60mg/kg body weight).DL1 group was treated with Losartan [20mg/(kg·d),ig] for 8 weeks immediately after the diabetic mould was made,while DL2 group began their treatment 8 weeks later.At the end of the 16th week,all rats were sacrificed,the left kidney was removed and weighed.Mean glomerular volume (MGV) and fractional mesangial area (FMA) were calculated by medical image analysis system.The mRNA expression of TGFβ1,CTGF,PAI1 and FN were detected by quantitative real time RTPCR.Urinary albumin excretion rate (UAER),as well as serum creatinine (SCr) and creatinine clearance rate (CCr),was detected.Results Compared with NC group,UAER increased 12.68 folds at the end of the 8thweek and 21.92 folds at the end of the 16thweek in group DN.At the same time,Scr in rats of group DN elevated significantly (136%),KW/BW,MGV and FMA in DN elevated significantly,which were 129%,98% and 183% higher separately,and the mRNA expression of TGFβ1,CTGF,PAI1 and FN in DN group increased 22.92,13.42,28.61 and 5.96 folds separately. All these indices decreased in rats of group DL1 and DL2 (P<0.05). And there was no significant differences between group DL1 and DL2(P>0.05). However,Ccr in rats of group DN began to decline already at the end of the 16th week (14.8%,P<0.05),which in rats of all treated diabetic groups was still higher than that in group NC (P<0.05).③FMA is negatively correlated with Ccr in rats of group DN at the 16th week.And the mRNA expression level of TGFβ1,CTGF,PAI1 and FN is positively correlated with UAER,KW/BW,MGV and FMA.Conclusion The mRNA expression level of TGF-β1,CTGF,PAI1 and FN is higher in kidneys of diabetic rats,which was responsible for renal hypertrophy,excess ECM deposition and increased UAER.Losartan could downregulate the mRNA expression of such renal cytokines,therefore prevent the progress of DN.The therapeutic effect is similar no matter we began treatment before or after microalbuminuria,which suggested that microalbuminuria be the appropriate time to begin clinical treatment of DN. ......
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