过刊浏览

卡托普利所致肾脏损害：肾小球入球动脉对血管紧张素II反应和炎症信号的相关研究

周素晗¹, 黄倩¹, 周莹², 蔡晓霞³, 崔瑜¹, 周琴¹, 郭洁¹, 姜山¹, 陈江华¹, 李玲莉⁴, 赖蒽茵^1,*, 赵亮⁵

¹浙江大学医学院附属第一医院肾脏病中心，基础医学院生理系，杭州 310003；²赣南卫生健康职业学院药学系，赣州 341000；³红河卫生职业学院基础医学院，蒙自 661199；⁴乔治城大学肾病与高血压科，华盛顿特区 20007，美国；⁵浙江大学医学院附属儿童医院，国家儿童健康与疾病临床医学研究中心，国家儿童区域医疗中心，杭州 310052

摘要

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C57Bl/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(preglomerular 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-2 mRNA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。

关键词： 卡托普利; 血管紧张素转换酶-1; 血管紧张素II; 肾传入小动脉; 肾损伤

Captopril related kidney damage: renal afferent arteriolar responses to angiotensin II and inflammatory signaling

ZHOU Su-Han¹, HUANG Qian¹, ZHOU Ying², CAI Xiao-Xia³, CUI Yu¹, ZHOU Qin¹, GUO Jie¹, JIANG Shan¹, CHEN Jiang-Hua¹, LI Ling-Li⁴, LAI En-Yin^1,*, ZHAO Liang⁵

¹Kidney Disease Center of First Affiliated Hospital, and Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310003, China；²Department of Pharmacology, Gannan Healthcare Vocational College, Ganzhou 341000, China；³School of Basic Medical Sciences, Honghe Health Vocational College, Mengzi 661199, China；⁴Division of Nephrology and Hypertension, Georgetown University, Washington DC 20007, USA；⁵National Clinical Research Center for Child Health, National Children’s Regional Medical Center, the Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China

Abstract

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. C57Bl/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, compared 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.

Key words: captopril; angiotensin converting enzyme-1; angiotensin II; renal afferent arteriole; kidney injury

收稿日期：　　录用日期：

通讯作者：赖蒽茵　　E-mail: laienyin@zju.edu.cn

DOI: 10.13294/j.aps.2022.0001

引用本文：

周素晗, 黄倩, 周莹, 蔡晓霞, 崔瑜, 周琴, 郭洁, 姜山, 陈江华, 李玲莉, 赖蒽茵, 赵亮. 卡托普利所致肾脏损害：肾小球入球动脉对血管紧张素II反应和炎症信号的相关研究[J]. 生理学报 2022; 74 (1): 125-133.

ZHOU Su-Han, HUANG Qian, ZHOU Ying, CAI Xiao-Xia, CUI Yu, ZHOU Qin, GUO Jie, JIANG Shan, CHEN Jiang-Hua, LI Ling-Li, LAI En-Yin, ZHAO Liang. Captopril related kidney damage: renal afferent arteriolar responses to angiotensin II and inflammatory signaling. Acta Physiol Sin 2022; 74 (1): 125-133