文章摘要
罗来敏,周红霞.前列环素衍生物对慢性肾衰大鼠肾脏局部RAS系统关键因子表达的影响[J].南京医科大学学报,2018,(3):310~316
前列环素衍生物对慢性肾衰大鼠肾脏局部RAS系统关键因子表达的影响
Effects of prostacyclin derivatives on the expression of key factors in renal local RAS system of rats with chronic renal failure
投稿时间:2017-02-21  
DOI:10.7655/NYDXBNS20180306
中文关键词: 慢性肾衰竭  前列环素  AngⅡ  Ang(1⁃7)  ACE2  AT1R
英文关键词: chronic renal failure  prostacyclin  AngⅡ  Ang(1⁃7)  ACE2  AT1R
基金项目:江西省科学技术厅科技支撑计划(20133BBG70060)
作者单位
罗来敏 南昌大学第一附属医院肾内科江西 南昌 330006 
周红霞 南昌大学第一附属医院肾内科江西 南昌 330006 
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中文摘要:
      目的:建立慢性肾衰竭(chronic renal failure,CRF)大鼠模型,研究前列环素(prostacyclin,PGI2)衍生物对CRF大鼠肾脏局部肾素—血管紧张素系统(renin angiotensin system,RAS)关键因子血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)、血管紧张素(1?7)[angiotensin(1?7),Ang?(1?7)]、血管紧张素转化酶2(angiotensin converting enzyme 2,ACE2)、血管紧张素1型受体(angiotensin Ⅱ type 1 receptor,AT1R)表达的影响,探索PGI2衍生物对大鼠CRF的可能保护机制。方法:清洁级雄性大鼠30只,按1∶2分为假手术组及手术组。手术组行5/6肾切除术后,第5周通过生化及病理检查确定造模成功,再将手术组按1∶1随机分成模型组及治疗组。自术后第5周,治疗组予PGI2衍生物贝前列素钠片(beraprost sodium,BPS)0.6 mg/(kg·d),分2次灌胃,模型组和假手术组大鼠给予等量蒸馏水。治疗4周后检测大鼠血清肌酐、尿素氮,收集24 h尿液测24 h尿蛋白量(24 hUPE)。随后处死大鼠,HE及Masson染色观察各组大鼠肾脏病理改变,采用实时定量聚合酶链反应(qRT?PCR)、Western blot、免疫荧光检测肾组织ACE2、AT1R表达,ELISA检测肾组织中Ang Ⅱ、Ang(1?7)浓度及血清中ACE2、AngⅡ、Ang(1?7)、AT1R的浓度变化。结果:术后5周和9周时手术组尿蛋白、血清肌酐、尿素氮均高于假手术组,差异有统计学意义。与术后5周时相比,术后9周时治疗组血清肌酐、尿素氮不同于模型组的明显下降,而仅仅是轻度下降,且高于模型组术后9周水平,蛋白尿的变化则相反。肾脏病理可见手术组出现系膜细胞增生、基质增生,肾间质炎性细胞浸润,间质纤维化,肾小球硬化等改变,而治疗组上述变化有所改善。手术组肾脏局部AngⅡ、AT1R较假手术组上调,而Ang(1?7)、ACE2则下调;与模型组相比,给予PGI2后,治疗组这4种RAS系统因子的变化趋势均减弱,差异有统计学意义,而血清中这4种RAS系统因子的变化与肾脏局部不同。结论:PGI2衍生物能减少CRF大鼠模型24 h尿蛋白定量,减轻肾脏慢性纤维化,可能延缓慢性肾脏病进展,其机制可能是通过调控CRF大鼠模型肾脏局部RAS系统关键因子AngⅡ、ACE2、Ang(1?7)、AT1R来实现的。
英文摘要:
      Objective:To establish a chronic renal failure(CRF)rat model and to investigate the effects of prostacyclin(PGI2)derivatives on the expressions of key factors in renal local renin angiotensin system(RAS)of CRF rats,including angiotensin Ⅱ(AngⅡ),angiotensin(1?7)[Ang?(1?7)],angiotensin converting enzyme 2(ACE2),and angiotensin Ⅱ type 1 receptor(AT1R),thereby to explore the potential protective mechanism of prostacyclin derivatives on CRF. Methods:A total of 30 SD male rats were divided into the sham operation group and the operation group at a ratio of 1∶2. Rats in the operation group underwent 5/6 nephrectomy followed by biochemical and pathological examinations 5 weeks after the surgery to determine the success of modeling,and then the operation group was further randomized into the model group and the treatment group at a ratio of 1∶1. Rats in the treatment group were given beraprost sodium(BPS),a PGI2 derivative at a dosage of 0.6 mg/(kg·d) through two intragastric administrations from the fifth week after operation,and those in the model group and the sham operation group received same volume of distilled water. After 4 weeks of treatment,serum creatinine(Scr)and urea nitrogen(BUN)were detected,and 24?hour urine protein excretion(24 hUPE)was measured. The rats were then sacrificed and pathological changes of renal tissues in rats were observed by HE and Masson staining. Expressions of ACE2 and AT1R in renal tissues were detected by real?time quantitative polymerase chain reaction(qRT?PCR),Western blot and immunofluorescence,and enzyme linked immunosorbent assay(ELISA)was employed to measure the expressions of AngⅡ and Ang(1?7)in kidey and ACE2,AngⅡ,Ang(1?7)and AT1 in serum. Results:24hUPE,Scr and BUN levels were higher in the operation group at 5 weeks and 9 weeks than those in the sham group,with statistical significance. Compared to levels at 5 weeks,Scr and BUN were remarkably decreased in the treatment group at 9 weeks,significantly different from those in the model group with mild reduction,but still higher than those of the model group at 9 weeks,whereas urine protein changed in the opposite direction. Renal pathology showed mesangial cell proliferation and matrix hyperplasia in the operation group,accompanied with changes such as renal interstitial inflammatory cell infiltration,interstitial fibrosis and glomerular sclerosis,on the contrary,above changes were improved in the treatment group. AngⅡ and AT1R in the kidney of the operation group were up?regulated than those in the sham operation group,but Ang(1?7)and ACE2 were down?regulated at the same time. Meanwhile,there were statistical differences in changes of the four factors in RAS in the treatment group,yet no such changes in the kidney were found in the serum. Conclusion:Prostacyclin derivatives reduce the 24 hUPE,relieve the chronic renal fibrosis,and possibly delay the progress of chronic kidney disease via a potential mechanism of regulating the expressions of key factors AngⅡ,ACE2,Ang(1?7) and AT1R in renal local RAS system in the CRF rat model.
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