罗格列酮减轻阿霉素肾病大鼠肾小球硬化的实验观察

目的观察罗格列酮干预治疗对单侧肾切除加重复阿霉素注射诱导的肾小球硬化大鼠肾脏的保护作用。方法建立单侧肾切除加重复阿霉素注射的肾小球硬化大鼠模型,分为罗格列酮治疗组和肾病组,设假手术组为对照组。检测各组大鼠第0、4、8、12周尿蛋白,并观察第12周肾组织病理改变,计算肾小球硬化指数。结果罗格列酮治疗组比肾病组尿蛋白排泄量明显减少(P<0.01),肾小球硬化程度明显减轻。结论罗格列酮对阿霉素肾病大鼠肾脏病变具有保护作用。     

吡格列酮对STZ糖尿病大鼠肾组织氧化应激的影响

目的观察不同剂量盐酸吡格列酮对STZ诱导的糖尿病大鼠肾组织氧化应激的影响。方法 STZ腹腔注射建立糖尿病大鼠模型。成模糖尿病大鼠随机分为模型组和不同剂量吡格列酮组,并设正常对照组,干预8周后检测肾皮质MDA含量,SOD活性,肾组织NADPH氧化酶亚单位p22phoxmRNA和p47phox mRNA表达。结果各吡格列酮组较模型组MDA含量,p22phox mRNA和p47phox mRNA表达明显降低,SOD活性明显升高(P<0.05)。结论吡格列酮可抑制STZ糖尿病大鼠肾脏NADPH氧化酶表达,降低肾脏氧化应激水平,并具有一定的剂量依赖性,该作用可能与其肾脏保护部分有关。     

吡格列酮对糖尿病大鼠肾脏的保护作用及其机制探讨

目的观察吡格列酮对糖尿病大鼠肾脏的保护作用并探讨其机制。方法采用链脲佐菌素(STZ)诱导糖尿病模型。24只大鼠随机分为正常对照组(NC组)、糖尿病组(DM组)、吡格列酮干预组(3mg·kg-1·d-1,DT组),每组8只。12周末,测定各组相关生化指标。运用比色法检测肾皮质中丙二醛(MDA)的含量、铜锌超氧化物歧化酶(Cu-ZnSOD)及过氧化氢酶(CAT)的活性。同时留取肾标本作电镜观察。结果与NC组相比,DM组和DT组血糖、胆固醇、甘油三酯、血清胰岛素、C肽、尿素氮、血肌酐、肾重/体重和24h尿蛋白定量差异有统计学意义。DM组与NC组比较,肾皮质Cu-ZnSOD、CAT活性明显降低(P<0.01),MDA含量明显增加(P<0.01)。DT组与DM组比较,血糖、胆固醇、甘油三酯、血清胰岛素、C肽、尿素氮、血肌酐差异无统计学意义(P>0.05),肾重/体重和24h尿蛋白定量明显降低(P<0.05);肾皮质CAT和Cu-ZnSOD活性增加(P<0.05),肾皮质MDA含量降低(P<0.05)。结论吡格列酮对糖尿病大鼠肾脏有保护作用且此作用不依赖其降糖、降脂机制,可能与吡格列酮的抗氧化机制有关。     

罗格列酮对阿霉素致肾小球硬化症大鼠的尿蛋白排泌量及肾小球蛋白(synaptopodin)表达的影响

目的 观察罗格列酮(胰岛素增敏药)对阿霉素致肾病大鼠的尿蛋白排泌量及肾小球蛋白表达的影响.方法 用罗格列酮治疗阿霉素诱导的局灶节段性肾小球硬化(FSGS)大鼠模型;用双缩脲法动态检测大鼠24 h尿蛋白量;分别用荧光实时定量PCR和免疫组织化学法检测大鼠肾组织synaptopodin mRNA和蛋白表达量.结果 罗格列酮能显著减缓FSGS大鼠尿蛋白排泄量的增加(P＜0.05);恢复大鼠肾组织蛋白表达量(P＜0.05),而不影响其mRNA表达量(P＞0.05);FSGS大鼠肾组织蛋白表达量与尿蛋白排泄量呈负相关(P＜0.01).结论 罗格列酮能减轻FSGS模型尿蛋白排泌量,其机制可能部分与维持足细胞足突肌动蛋白微丝骨架系统的稳定有关.     

氧化应激在糖尿病肾病中的意义及吡格列酮干预研究

目的观察糖尿病大鼠肾脏组织中氧化应激水平,探讨氧化应激在糖尿病肾病中的作用及吡格列酮干预效果。方法采用链脲佐菌素(STZ)诱导糖尿病模型。24只大鼠随机分为正常对照组(NC组)、糖尿病组(DM组)、吡格列酮干预组(3mg·kg-1.d-1,DT组),每组8只。12周末,测定各组相关生化指标。运用比色法检测肾皮质中丙二醛(MDA)的含量、铜锌超氧化物歧化酶(Cu-ZnSOD)及过氧化氢酶(CAT)的活性。结果与NC组相比,DM组和DT组血糖、胆固醇、甘油三酯、尿素氮、血肌酐、肾质量/体质量和尿蛋白定量(24h)值差异有统计学意义。DM组与NC组比较,肾皮质Cu-ZnSOD、CAT活性明显降低(P<0.01),MDA含量明显增加(P<0.01)。DT组与DM组比较,血糖、胆固醇、甘油三酯、尿素氮、血肌酐值差异无统计学意义(P>0.05),肾质量/体质量和尿蛋白定量(24h)明显降低(P<0.05);肾皮质CAT和Cu-ZnSOD活性增加(P<0.05),肾皮质MDA含量降低(P<0.05)。结论糖尿病大鼠肾脏组织中氧化应激水平升高,在糖尿病肾病发病机制中起重要作用。吡格列酮可能通过抗氧化作用改善糖尿病大鼠肾脏损害。     

苦参素对阿霉素肾病肾硬化大鼠细胞凋亡及Bax、Bcl-2表达的影响

目的 探讨苦参素对阿霉素肾病肾硬化大鼠细胞凋亡及凋亡相关蛋白Bax 和Bcl-2 表达的影响.方法 60只Wistar大鼠随机分为4组:正常对照组、氧化苦参碱50 mg·kg-1·d-1治疗组、氧化苦参碱100 mg·kg-1·d-1治疗组、模型组.分2次(间隔21 d)尾静脉注射阿霉素(每次2 mg/kg)构建肾病慢性病理进展模型.第2次注药后各干预组予以相应的药物进行灌胃,之后每8周每组杀鼠5只观察大鼠尿蛋白、血清指标、肾脏病理、肾组织细胞凋亡及Bax、Bcl-2蛋白的表达.动物实验时间27周.结果 各干预组比模型组尿蛋白排泄量明显减少,血肌酐和尿素氮水平下降,肾小球系膜增生、硬化程度及细胞凋亡明显减轻(P＜0.05或P＜0.01);肾小球内Bax蛋白沉积较模型组明显减少,Bcl-2蛋白的沉积较模型组明显增多(P＜0.01).结论 苦参素减轻阿霉素肾病鼠慢性肾脏损害的机理可能与其抑制肾脏细胞凋亡有关.     

吡格列酮对Aβ25-35所致痴呆大鼠的学习记忆能力及海马内氧化应激的影响

目的 研究吡格列酮对Aβ25-35所致痴呆大鼠学习记忆能力和海马内氧化应激反应的影响.方法 侧脑室注射Aβ25-35建立大鼠AD模型,吡格列酮(40mg/kg、80 mg/kg)灌胃21d,次日行Morris水迷宫实验,前5天定位航行训练,第6天进行空间探索实验.行为学实验后第2天麻醉,断头取脑,提取脑组织匀浆,以备ELISA实验.ELISA实验研究大鼠海马内的氧化应激反应.结果 Morris水迷宫结果显示,模型组大鼠潜伏期较空白对照组明显延长,而穿过平台次数和平台滞留时间缩短.经吡格列酮治疗后,潜伏期显著缩短,穿过平台次数和滞留时间也相应增加.ELISA结果显示,模型组大鼠海马内酶性抗氧化剂GSH-Px和SOD活性较空白对照组明显降低,而脂质过氧化产物MDA含量增加.经吡格列酮治疗后,GSH-Px和SOD活性提高,MDA产生减少.结论 吡格列酮能改善痴呆大鼠的学习记忆能力,其机制可能与对抗海马内的氧化应激反应有关.     

吡格列酮对糖尿病大鼠肾脏氧化应激的影响

目的:研究吡格列酮对糖尿病大鼠肾组织氧化应激的影响。方法:采用链脲佐菌素诱导糖尿病模型,随机分为正常对照组、正常对照治疗组、糖尿病组、糖尿病治疗组,两治疗组给予吡格列酮10 mg.kg-1.d-1灌胃,1次/d,每组10只。后两组大鼠糖尿病模型构建成功后的第10周末测定血糖、肾重/体重2、4 h尿蛋白定量,并检测肾组织中丙二醛(MDA)、总抗氧化能力(T-AOC)、谷胱甘肽(GSH)的含量,及肾组织铜锌超氧化物歧化酶(Cu,Zn-SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)、谷胱甘肽还原酶(GR)的活性。结果:糖尿病治疗组与糖尿病组比较,血糖无显著差异(P>0.05),但肾重/体重和24 h尿蛋白定量明显降低(P<0.01);与正常对照组相比,糖尿病组肾组织MDA含量、CAT活性明显增加(P<0.01),T-AOC、GSH含量和Cu,Zn-SOD、GSH-Px、GR活性明显降低(P<0.01);与糖尿病组比较,糖尿病治疗组肾组织MDA含量和CAT活性明显降低(P<0.05,P<0.01),T-AOC、GSH含量和Cu,Zn-SOD、GSH-Px、GR活性明显增加(P<0.01)。结论:糖尿病大鼠肾脏存在明显氧化应激反应,吡格列酮具有不依赖其降糖效果的抗氧化活性,进而起到保护肾脏和延缓糖尿病肾病发生、发展的作用。     

辛伐他汀对阿霉素肾病大鼠的肾脏保护作用

目的:观察辛伐他汀对阿霉素肾病大鼠的肾脏保护作用.方法:雄性SD大鼠24只随机分为正常对照组、阿霉素肾病组(模型组)和阿霉素肾病辛伐他汀治疗组(治疗组),一次性尾静脉注射阿霉素6.5 mg/kg建立肾病大鼠模型.治疗组每日给予辛伐他汀(3 mg/kg)灌胃,对照组和模型组每日灌等量生理盐水,分别灌胃11周,于注射阿霉素后第12周末结束实验.考马斯亮蓝法检测24 h尿蛋白定量,全自动生化仪检测血清生化学指标,光镜和电镜观察肾组织病理形态学变化,统计肾小球硬化指数.结果:模型组24 h尿蛋白定量、血脂、血肌酐水平及肾小球硬化指数明显高于对照组,辛伐他汀明显降低阿霉素肾病大鼠24 h尿蛋白、血肌酐水平及肾小球硬化指数(P<0.01).治疗组和模型组血脂差异无统计学意义.结论:辛伐他汀可以不依赖于其降血脂的效应,对阿霉素肾病大鼠发挥肾脏保护作用.     

罗格列酮延缓慢性肾病进展的机制研究

目的 探讨过氧化物酶体增殖物激活受体γ(PPARγ)激动药罗格列酮对5/6肾切除肾衰竭大鼠的肾脏保护作用及可能作用机制.方法选用180～200 g健康雄性SD大鼠建立5/6肾切除肾衰竭模型,分为假手术组、模型对照组和罗格列酮组.第12周时采用断头法处死大鼠,并检测各组大鼠血清尿素氮、肌酐及24 h尿蛋白水平;取残余肾组织行病理检查,判断肾小球硬化、肾小管间质损伤程度;采用免疫组化方法观察PPARγ和神经型一氧化氮合酶(nNOS)在肾脏组织的分布;利用RT PCR和Western Blot检测PPARγ和nNOS 蛋白和mRNA的表达水平.结果与假手术组比较,模型对照组和罗格列酮组大鼠24 h尿蛋白、血清尿素氮及肌酐均显著升高(P＜0.01);但与模型对照组比较,罗格列酮组各指标则明显降低(P＜0.05).病理学检查示模型对照组大鼠肾组织有明显的肾小球硬化及肾小管间质损伤,肾小球硬化指数及肾小管间质损伤指数均较假手术组明显增高(P＜0.01);而罗格列酮组上述指标则较模型对照组明显降低(P＜0.05).免疫组化结果显示5/6肾切除大鼠PPARγ主要分布在肾小管上皮细胞、系膜细胞和浸润的巨噬细胞,nNOS主要定位在致密斑,内髓集合管也有表达.模型对照组PPARγ、nNOS蛋白和mRNA的表达较假手术组明显下降(P＜0.05),而罗格列酮组PPARγ和nNOS的表达则较模型对照组明显升高(P＜0.05).结论大鼠5/6肾切除后,给予罗格列酮可以明显减轻肾小球硬化和肾间质纤维化的程度,其作用机制可能与其上调PPARγ和nNOS基因的表达有关,且有明显的相关性.     

肾脏组织中TGF-β1和CTGF对NF-κB基因调控的影响

目的 研究阿霉素肾病大鼠模型中核因子-κB(NF-κB)、转化生长因子β1(TGF-β 1)和结缔组织生长因子(CTGF)的浓度与病理变化的意义,探讨其参与肾病综合征的发病机制.方法 36只大鼠随机分成两组:对照组、模型组,每组各18只.模型组采用尾静脉注射阿霉素方法建立阿霉素肾病模型.检测各组大鼠24 h尿蛋白定量及血清肾功能指标,研究各组大鼠肾组织病理学改变,采用免疫学方法(ELISA)检测NF-κB、TGF-β1及CTGF浓度的变化.结果 ①模型组于第2、4、6周尿蛋白定量均高于同期对照组,差异有统计学意义(P＜ 0.01).第2、4、6周时模型组血尿素氮(BUN)及肌酐(Scr)、胆固醇(TC)水平均高于同期对照组(P＜0.01).②肾组织病理学提示随时间延长,肾病病理进展.③模型组第2、4、6周NF-κB、TGF-β1和CTGF浓度结果均高于同期对照组(P＜0.01).结论 NF-κB、TGF-β1和CTGF浓度增高是肾小球硬化发生发展的重要因素,三者共同促进细胞外基质(ECM)的积聚,造成肾小球硬化.阻断NF-κB、TGF-β1和CTGF可能成为延缓肾小球硬化的治疗手段.     

补肾活血方对阿霉素肾病小鼠肾小球足细胞nephrin表达的影响

【摘要】 目的 观察补肾活血方治疗对阿霉素(ADR)诱导的阿霉素肾病小鼠肾小球足细胞裂孔膜蛋白nephrin表达的影响,并探讨其作用机制。方法 用ADR诱导产生局灶性节段性肾小球硬化(FSGS)肾病模型,1周后用补肾活血方治疗(治疗组),持续6周。并设空白对照组、模型组。收集各组血、尿及肾组织,检测其体质量、右肾质量、血清白蛋白(ALB)、尿白蛋白/尿肌酐比值(UACR)。光镜观察肾组织形态改变;免疫荧光测定小鼠肾小球足细胞nephrin的表达;RT-PCR检测各组肾组织nephrin mRNA的表达。结果 模型组UACR显著高于对照组与治疗组,体质量和ALB显著低于对照组和治疗组(均P<0.01);对照组肾小球足细胞nephrin免疫荧光呈连续性表达,治疗组呈轻微缺失,模型组呈少量点状或片状表达,较对照组和治疗组表达强度明显减少。模型组nephrin mRNA表达水平均显著低于对照组和治疗组(P<0.01)。结论 补肾活血方能减少阿霉素肾病小鼠的蛋白尿,可能与改善肾小球足细胞nephrin的表达减少有关。     

他克莫司对肾小球硬化核转录因子-kB的影响

目的 检测大鼠肾组织核转录因子-kB(NF-kB)的表达,探讨他克莫司对阿霉素肾病大鼠NF-kB的影响.方法 SD雄性大鼠18只分为3组,A组(正常对照组)、B组(模型组)、C组(干预组),每组6只.采用尾静脉注射阿霉素法作肾小球硬化动物模型.第4周各组大鼠予不同药物干预,给药后2周及4周分别检测各组大鼠24 h尿蛋白,观察其肾组织形态学变化,计算肾小球硬化指数(GI),应用免疫组织化学检测其肾组织NF-kB p65的表达.结果 在不同时间点,B组尿蛋白、GI、NF-kB p65的表达与A组比较均显著升高.在4周时间点,C组的NF-kB p65的表达与B组比较显著降低,与A组比较无统计学差异.他克莫司的干预效应较2周时间点强.结论 他克莫司可抑制肾组织NF-kB的活性,抑制肾小球系膜细胞的炎性反应,从而延缓肾小球硬化进程.     

全反式维甲酸与苯那普利对肾硬化大鼠肾脏组织α-SMA表达的影响

目的研究全反式维甲酸(ATRA)与苯那普利对肾硬化大鼠肾脏组织α-SMA表达的影响。方法80只Wistar♂大鼠随机分为假手术组、模型组、苯那普利组和ATRA组,每组均为20只。采用单侧肾切除加1wk后尾静脉注射阿霉素(5mg·kg-1)的方案建立大鼠肾小球硬化(GS)模型,造模后12wk末处死。HE染色观察肾脏病理改变,计算肾小球硬化指数(GSI)。RT-PCR结合免疫组织化学方法检测肾组织α-平滑肌肌动蛋白(α-SMA)的表达情况。结果与模型组相比,ATRA组和苯那普利组GSI、α-SMA mRNA相对表达量和α-SMA阳性面积比均明显下降(P<0.05),但两组间各项指标比较无差异(P>0.05)。结论ATRA与苯那普利对大鼠肾硬化均有明显的延缓效应,且疗效一致。     

The progression of adriamycin-induced nephrotic syndrome in rats and the effect of captopril

The progression of adriamycin-induced nephrotic syndrome in rats was studied over a 3-month period. The effect of an angiotensin-converting enzyme inhibitor, captopril, on this model of renal disease, was also studied. Two weeks following a single iv injection of adriamycin, rats were divided into two treatment groups: one received a daily po dose of captopril and the other received a placebo. Measurements of renal function were performed at 4, 8, and 11 weeks following the initiation of therapy. Necropsies and light microscopic evaluation of the kidneys were performed at the end of the treatment period. Functional and morphologic alterations in both groups of rats were compared to each other and to normal age/weight-matched control rats studied over the same time period. At 13 weeks following the administration of adriamycin, both treatment groups had significant renal dysfunction when compared to normal controls. In addition to severe proteinuria, rats receiving adriamycin exhibited polyuria, polydipsia, increased plasma urea nitrogen and plasma creatinine, and decreased endogenous creatinine clearance. They had severe generalized kidney lesions characterized by tubular dilation and atrophy, cast formation, interstitial fibrosis and lymphocytic infiltration, and focal, global glomerulosclerosis. The histopathologic ranking of the kidneys was correlated with some antemortem laboratory parameters but not with the degree of proteinuria. Captopril had no ameliorating effects on the progression of renal disease. Certain findings indicate that captopril may actually have promoted the deterioration of renal function. We conclude that adriamycin-induced nephrotic syndrome in the rat is a progressive disease resulting in generalized renal dysfunction, and that captopril, at the dose given in this experiment, is unable to slow the progression of the disease.     

Pharmacodynamics of Yuebi Jiazhu Decoction on renal protection of adriamycin nephropathy rats

In the present study, we aimed to investigate the protective effect of Yuebi Jiazhu Decoction (YBJZD) on the kidney of adriamycin nephropathy (AN) rats. Rats were injected with adriamycin for modeling, except for the control group. After the successful establishment of the animal model, rats were randomly divided into the model group, YBJZD low-, medium-, and high-dose groups, and the positive group. The 24-h urine samples were collected. Biochemical indicators were monitored, and kidney tissues were collected for pathological analysis using light microscopy. The results showed that through 4 weeks of drug intervention, the urinary protein level was lower in the YBJZD and positive groups compared with the model group (P < 0.05). Serum levels of BUN, SCr, and TG were significantly lower (P < 0.01), and ALB was significantly higher (P < 0.01) in the YBJZD and positive groups compared with the model group. Compared with the model group, the pathological injury of kidney tissue in the YBJZD and positive groups was significantly alleviated. These outcomes proved that YBJZD had a renal protective effect on AN rats.     

曲尼司特对阿霉素肾病大鼠肾脏TIMP-1、FN表达的影响

目的研究曲尼司特对阿霉素肾病肾小球硬化大鼠的肾脏保护作用,并探讨其可能的机制。方法SD大鼠24只,随机分为正常对照组、模型组、曲尼司特组和安博维组,采用单侧肾切除加尾静脉注射阿霉素的方法建立阿霉素肾病模型。观察各组大鼠24h尿蛋白定量、BUN、Scr及肾脏病理的改变。应用免疫组化方法测定肾组织TIMP-1、FN的表达。结果曲尼司特能减少阿霉素肾病大鼠的尿蛋白,延缓Scr上升;减轻基质增生和肾小球硬化;下调阿霉素肾病大鼠肾组织中TIMP-1、FN的表达。结论曲尼司特可能通过下调阿霉素肾病大鼠肾组织中TIMP-1、FN的表达,调节细胞外基质的生成与降解,从而减轻肾脏病理损害,发挥其肾脏保护作用。     

All-trans retinoic acid can regulate the expressions of gelatinases and apolipoprotein E in glomerulosclerosis rats

Apolipoprotein E (apoE) is an important plasma protein in cholesterol homeostasis and plays a key role in the pathogenesis of glomerulosclerosis (GS). Gelatinases include matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The abnormal expressions of gelatinases are implicated in the pathogenesis of extracellular matrix accumulation. All-trans retinoic acid (ATRA) is an import biological agent which can play a protective role against GS. We performed this investigation to explore whether ATRA could regulate the expressions of gelatinases and apoE in the glomerulus of GS rats. 120 Wistar rats were randomly divided into three groups: sham operation group (SHO), glomerulosclerosis model group without treatment (GS) and GS model group treated with ATRA (GA). The GS disease was established by uninephrectomy and adriamycin injection. At the end of 9 and 13weeks, the relevant samples were collected and determined. Compared with GS group at 9/13weeks, values of 24-hour urine total protein, 24-hour urine excretion for albumin, blood urea nitrogen, serum creatinine and glomerulosclerosis index, and protein expressions of apoE, transforming growth factor-βl (TGF-β1), α-smooth muscle actin, collagen-IV and fibronectin in glomerulus and mRNA expressions of apoE and TGF-β1 in renal tissue were significantly down-regulated by ATRA (each P<0.01). However, the expressions of MMP-2 and MMP-9 (mRNA, protein and activity) were enhanced in GA group than those in GS group. In conclusion, gelatinases are associated with apoE expression, and ATRA can increase the gelatinases expressions and reduce the accumulation of apoE in glomerulus of GS rats, but the detailed mechanism needs to be elucidated in the future.