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卡托普利可表现出一定的肾毒性作用,主要是源于该药物会造成肾素的累积和血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)的逃逸.本研究主要目的是探究血管紧张素转换酶1抑制剂卡托普利是否通过改变肾入球动脉对Ang Ⅱ的反应,同时激活炎性信号通路而损伤肾脏.用卡托普利(每天60 mg/kg)喂养C57B1/6小鼠四周,其中后两周用皮下植入Ang Ⅱ(400 ng/kg per min)微泵注射建立高血压小鼠模型.模型建成后,用PAS(periodic acid-Schiff)及Masson染色评估肾脏的病理改变,用FITC标记的菊粉清除率检测肾小球滤过率,用体外入球动脉灌注方式检测入球动脉对Ang Ⅱ反应,用试剂盒检测肾小球前小动脉(preglo-merular arterioles)的过氧化氢、过氧化氢酶水平和血浆肾素水平,用RT-qPCR检测肾皮质转化生长因子β(transforming growth factor-β,TGF-β),环氧合酶-2(cyclooxygenase-2,COX-2)和肾小球前小动脉血管紧张素受体mRNA表达水平.结果显示,与溶剂组小鼠相比,卡托普利组小鼠血压降低,肾小球滤过率下降,肾素分泌增多,出现肾间质纤维化和肾小管上皮空泡变性;肾皮质TGF-β和COX-2mRNA表达水平上调,球前血管过氧化氢产生减少,而过氧化氢酶的活性增加;Ang Ⅱ诱导的入球动脉收缩增强,而过氧化氢预孵育可减轻卡托普利组小鼠入球动脉对Ang Ⅱ的收缩反应.肾小球前小动脉血管紧张素受体1、2 mRNA表达水平不受卡托普利影响.Ang Ⅱ微泵植入小鼠血压升高,其入球动脉对Ang Ⅱ反应减弱.卡托普利处理的Ang Ⅱ微泵植入小鼠血压可恢复正常,但是其入球动脉对Ang Ⅱ反应不能恢复.以上结果提示,血管紧张素转换酶1抑制剂可加强肾脏微血管对Ang Ⅱ的敏感性,并且激活重要的炎性通路.“,”Captopril can have nephrotoxic effects,which are largely attributed to accumulated renin and “escaped” angiotensin Ⅱ(Ang Ⅱ).Here we test whether angiotensin converting enzyme-1(ACE1)inhibition damages kidneys via alteration of renal afferent arteriolar responses to Ang Ⅱ and inflammatory signaling.C57B1/6 mice were given vehicle or captopril(60 mg/kg per day)for four weeks.Hypertension was obtained by minipump supplying Ang Ⅱ(400 ng/kg per min)during the second 2 weeks.We assessed kidney histology by periodic acid-Schiff(PAS)and Masson staining,glomerular filtration rate(GFR)by FITC-labeled inulin clearance,and responses to Ang Ⅱ assessed in afferent arterioles in vitro.Moreover,arteriolar H2O2 and catalase,plasma renin were assayed by commercial kits,and mRNAs of renin receptor,transforming growth factor-β(TGF-β)and cyclooxygenase-2(COX-2)in the renal cortex,mRNAs of angiotensin receptor-1(AT1R)and AT2R in the preglomerular arterioles were detected by RT-qPCR.The results showed that,com-pared to vehicle,mice given captopril showed lowered blood pressure,reduced GFR,increased plasma renin,renal interstitial fibrosis and tubular epithelial vacuolar degeneration,increased expression of mRNAs of renal TGF-β and COX-2,decreased production of H2O2 and increased catalase activity in preglomerular arterioles and enhanced afferent arteriolar Ang Ⅱ contractions.The latter were blunted by incubation with H2O2.The mRNAs of renal microvascular AT1R and AT2R remained unaffected by captopril.Ang Ⅱ-infused mice showed increased blood pressure and reduced afferent arteriolar Ang Ⅱ responses.Administration of captopril to the Ang Ⅱ-infused mice normalized blood pressure,but not arteriolar Ang Ⅱ responses.We conclude that inhibition of ACE1 enhances renal microvascular reactivity to Ang Ⅱ and may enhance important inflammatory pathways.