Manipulation of components of the renin angiotensin system in renal proximal tubules fails to alter atherosclerosis in hypercholesterolemic mice.
Manipulation of components of the renin angiotensin system in renal proximal tubules fails to alter atherosclerosis in hypercholesterolemic mice.
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DOI：
10.3389/fcvm.2023.1250234
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发表时间：
2023
影响因子：
3.6
通讯作者：
Lu, Hong S.
中科院分区：
文献类型：
--
作者：
Kukida, Masayoshi;Amioka, Naofumi;Ye, Dien;Chen, Hui;Moorleghen, Jessica J.;Liang, Ching-Ling;Howatt, Deborah A.;Katsumata, Yuriko;Yanagita, Motoko;Sawada, Hisashi;Daugherty, Alan;Lu, Hong S.
关键词：
全身操作的肾素-血管紧张素系统（RAS）一贯发挥深远的影响实验性动脉粥样硬化的发展。文献中的一个缺陷是缺乏对性的影响的关注。此外，基于基因缺失小鼠的数据，影响病变形成的RAS活性位点位于未知的遥远位置。由于肾脏中血管紧张素（AngII）浓度较高，并且RAS的主要成分存在于肾近曲小管细胞（PTC）中，因此本研究评估了PTC中RAS在动脉粥样硬化发展中的作用。给具有LDL受体−/−背景的小鼠喂食西方饮食以诱导高胆固醇血症和动脉粥样硬化。我们首先证明了AT 1受体拮抗作用在两性动脉粥样硬化中的作用。氯沙坦，血管紧张素Ⅱ 1型（AT 1）受体阻滞剂，有更大的降低血压的作用，女性比男性，但在减少动脉粥样硬化病变大小的性别之间的效果相同。为了确定肾AT 1a受体和血管紧张素转换酶（ACE）的作用，在断奶后使用他莫昔芬诱导的Cre表达的Ndrg 1启动子的控制下，在PTC中删除任何一个组件。尽管PTCs中AT 1a受体或ACE的缺失，但这两种蛋白的缺失并不影响两种性别动脉粥样硬化的发展。相反，在PTC中表达人血管紧张素原和肾素或在肝脏中表达人血管紧张素原但在PTC中表达人肾素的小鼠没有改变雄性小鼠动脉粥样硬化病变的大小。在雄性和雌性小鼠中，全身AT 1 R抑制同等程度地减少动脉粥样硬化;然而，PTC特异性操作RAS组分对高胆固醇血症诱导的动脉粥样硬化没有影响。
Whole body manipulation of the renin-angiotensin system (RAS) consistently exerts profound effects on experimental atherosclerosis development. A deficit in the literature has been a lack of attention to the effects of sex. Also, based on data with gene-deleted mice, the site of RAS activity that influences lesion formation is at an unknown distant location. Since angiotensin (AngII) concentrations are high in kidney and the major components of the RAS are present in renal proximal tubule cells (PTCs), this study evaluated the role of the RAS in PTCs in atherosclerosis development. Mice with an LDL receptor −/− background were fed Western diet to induce hypercholesterolemia and atherosclerosis. We first demonstrated the role of AT1 receptor antagonism on atherosclerosis in both sexes. Losartan, an AngII type 1 (AT1) receptor blocker, had greater blood pressure-lowering effects in females than males, but equivalent effects between sexes in reducing atherosclerotic lesion size. To determine the roles of renal AT1a receptor and angiotensin-converting enzyme (ACE), either component was deleted in PTCs after weaning using a tamoxifen-inducible Cre expressed under the control of an Ndrg1 promoter. Despite profound deletion of AT1a receptor or ACE in PTCs, the absence of either protein did not influence development of atherosclerosis in either sex. Conversely, mice expressing human angiotensinogen and renin in PTCs or expressing human angiotensinogen in liver but human renin in PTCs did not change atherosclerotic lesion size in male mice. Whole-body AT1R inhibition reduced atherosclerosis equivalently in both male and female mice; however, PTC-specific manipulation of the RAS components had no effects on hypercholesterolemia-induced atherosclerosis.
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DOI：
10.1161/hypertensionaha.112.203679
发表时间：
2013-01
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
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通讯作者：
Coffman TM
DOI：
10.1161/atvbaha.115.306740
发表时间：
2016-02
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
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通讯作者：
Daugherty A
DOI：
10.3791/1291
发表时间：
2009-05-15
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
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通讯作者：
Balakrishnan, Anju
DOI：
10.36922/gtm.v1i1.76
发表时间：
2022-01-01
期刊：
Global translational medicine
影响因子：
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作者：
Chen, Hui;Howatt, Deborah A;Lu, Hong S
通讯作者：
Lu, Hong S
DOI：
10.1152/ajpregu.00124.2011
发表时间：
2011-10-01
影响因子：
2.8
作者：
Li, Huiping;Weatherford, Eric T.;Sigmund, Curt D.
通讯作者：
Sigmund, Curt D.