Li Xiao C, Navar L Gabriel, Shao Yuan, Zhuo Jia L
Laboratory of Receptor and Signal Transduction, Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI 48202, USA.
Am J Physiol Renal Physiol. 2007 Aug;293(2):F586-93. doi: 10.1152/ajprenal.00489.2006. Epub 2007 May 30.
We and others have previously shown that high levels of ANG II are accumulated in the rat kidney via a type 1 (AT(1)) receptor-mediated mechanism, but it is not known which AT(1) receptor is involved in this process in rodents. We tested the hypothesis that AT(1a) receptor-deficient mice (Agtr1a-/-) are unable to accumulate ANG II intracellularly in the kidney because of the absence of AT(1a) receptor-mediated endocytosis. Adult male wild-type (Agtr1a+/+), heterozygous (Agtr1a+/-), and Agtr1a-/- were treated with vehicle, ANG II (40 ng/min ip via osmotic minipump), or ANG II plus the AT(1) antagonist losartan (10 mg.kg(-1).day(-1) po) for 2 wk. In wild-type mice, ANG II induced hypertension (168 +/- 4 vs. 113 +/- 3 mmHg, P < 0.001), increased kidney-to-body weight ratio (P < 0.01), caused pressure natriuresis (P < 0.05), and elevated plasma and whole kidney ANG II levels (P < 0.001). Concurrent administration of ANG II with losartan attenuated these responses to ANG II. In contrast, Agtr1a-/- mice had lower basal systolic pressures (P < 0.001), smaller kidneys with much fewer AT(1b) receptors (P < 0.001), higher basal 24-h urinary sodium excretion (P < 0.01), as well as basal plasma and whole kidney ANG II levels (P < 0.01). However, intracellular ANG II levels in the kidney were lower in Agtr1a-/- mice. In Agtr1a-/- mice, ANG II slightly increased systolic pressure (P < 0.05) but had no effect on the kidney weight, urinary sodium excretion, and whole kidney ANG II levels. Losartan restored systolic pressure to basal levels and decreased whole kidney ANG II levels by approximately 20% (P < 0.05). These results demonstrate a predominant role of AT(1a) receptors in blood pressure regulation and in the renal responses to long-term ANG II administration, that AT(1b) receptors may play a limited role in blood pressure control and mediating intrarenal ANG II accumulation in the absence of AT(1a) receptors.
我们和其他人之前已经表明，高水平的血管紧张素II（ANG II）通过1型（AT(1)）受体介导的机制在大鼠肾脏中积累，但尚不清楚在啮齿动物中该过程涉及哪种AT(1)受体。我们检验了这样一个假设：由于缺乏AT(1a)受体介导的内吞作用，AT(1a)受体缺陷小鼠（Agtr1a-/-）无法在肾脏细胞内积累ANG II。成年雄性野生型（Agtr1a+/+）、杂合子（Agtr1a+/-）和Agtr1a-/-小鼠分别接受溶剂、ANG II（通过渗透微型泵腹腔注射，40 ng/min）或ANG II加AT(1)拮抗剂氯沙坦（10 mg·kg(-1)·day(-1)口服）治疗2周。在野生型小鼠中，ANG II诱导高血压（168±4 vs. 113±3 mmHg，P<0.001），增加肾重与体重比（P<0.01），引起压力性利钠（P<0.05），并升高血浆和全肾ANG II水平（P<0.001）。ANG II与氯沙坦同时给药减弱了对ANG II的这些反应。相比之下，Agtr1a-/-小鼠的基础收缩压较低（P<0.001），肾脏较小且AT(1b)受体少得多（P<0.001），基础24小时尿钠排泄较高（P<0.01），以及基础血浆和全肾ANG II水平较高（P<0.01）。然而，Agtr1a-/-小鼠肾脏中的细胞内ANG II水平较低。在Agtr1a-/-小鼠中，ANG II使收缩压略有升高（P<0.05），但对肾脏重量、尿钠排泄和全肾ANG II水平没有影响。氯沙坦将收缩压恢复到基础水平，并使全肾ANG II水平降低约20%（P<0.05）。这些结果表明，AT(1a)受体在血压调节以及对长期给予ANG II的肾脏反应中起主要作用，在缺乏AT(la)受体的情况下，AT(1b)受体在血压控制和介导肾内ANG II积累中可能起有限作用。
