氯沙坦对两肾一夹高血压大鼠肾脏的保护作用及PRCP-激肽释放酶调节轴的影响  

Effect of losartan on the protection of the kidney and PRCP-kallikrein axis of the two-kidney, one-clipped renovascular hypertensive rats

作　　者：秦又发[1,2] 田海红[1] 孙飞[1] 秦旭平[1] 

机构地区：[1]南华大学药物药理研究所,湖南衡阳421001 [2]随州市中心医院西药部,湖北随州441300

出　　处：《药学学报》2013年第1期59-65,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(30572192;81173060);南华大学归国人员基金资助项目(2010XQD446)

摘　　要：本研究观察氯沙坦对两肾一夹(2K1C)高血压大鼠体内脯氨酰羧基肽酶(PRCP)-激肽释放酶调节轴的影响,揭示氯沙坦保护肾脏作用的新机制。采用SD大鼠,建立2K1C高血压大鼠模型,分别给予哌唑嗪(5 mg.kg 1.d 1)或氯沙坦(5、15及45 mg.kg 1.d 1)连续干预4周,观察血压变化。实验结束后,通过计算大鼠右侧肾脏体重比,石蜡切片HE染色观察肾小球纤维化的程度以及自动生化分析仪检测血清中Na+、K+、肌酐以及尿素氮的含量来评估大鼠肾脏功能;RT-PCR分析右侧肾脏中PRCP mRNA的表达;Western blotting分析肾脏中PRCP、组织激肽释放酶、血浆激肽释放酶和TGF-β1以及血浆中血浆激肽释放酶蛋白的表达水平。结果显示,氯沙坦能显著减轻由高血压大鼠肾脏体重比、肾小球的融合及纤维化和血清生化指标的改变;并能同时升高其同侧肾脏组织中PRCP、血浆激肽释放酶和组织激肽释放酶的蛋白表达,降低TGF-β1蛋白的表达。氯沙坦对2K1C高血压大鼠肾脏功能的保护作用可能与其增强大鼠体内PRCP-血浆激肽释放酶和组织激肽释放酶调节轴功能、降低TGF-β1蛋白的表达有关。To investigate the effect of losartan on the axis of prolylcarboxypeptidase（PRCP） kallikrein of the two-kidney,one-clipped（2K1C） hypertensives rats,and explore the novel protection mechanism of losartan on the kidney.Sprague-Dawley（SD） rats were used to develop the 2K1C hypertensive rats.Then,the rats were treated with prazosin（5 mg.kg 1.d 1） or losartan（5,15 and 45 mg.kg 1.d 1） or vehicle,separately.At the same time,the blood pressures were observed.After treated for four weeks,the ratio of right kidney weight and body weight,the change of glomerular morphology,and K＋,Na＋,creatinine and blood urea nitrogen（BUN） of the serum were used for evaluation of kidney.The expressions of PRCP mRNA in the kidneys were determined by RT-PCR.The protein levels of PRCP,tissue kallikrein,plasma kallikrein,TGF-β1 in kidney or plasma were measured by Western blotting.Results showed that the changes of body weight and kidney weight ratio,glomerular fibrosis degree and the biochemistrical index of serum induced by hypertension were relieved when the hypertensive rats treated with losartan for four weeks.Meanwhile,treatment of losartan also significantly decreased expression of TGF-β1 and increased expressions of PRCP,plasma kallikrein and tissue kallikrein.The protective effects of losartan on the kidney of 2K1C hypertensive rats are activation of the axis of PRCPkallikrein and reducing the expression of TGF-β1.

关 键 词：氯沙坦 两肾一夹高血压大鼠 肾脏 脯氨酰羧基肽酶 血浆激肽释放酶 组织激肽释放酶 转化生长因子β1 

分 类 号：R965[医药卫生—药理学]