Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Hypertension. 2010 Jan;55(1):166-71. doi: 10.1161/HYPERTENSIONAHA.109.141622. Epub 2009 Nov 30.
The angiotensin (Ang) type 1 receptor (AT(1)R) is highly expressed on renal nuclei and stimulates reactive oxygen species (ROS). It is not known whether other functional components of the Ang system regulate the nuclear Ang II-AT(1)R ROS pathway. Therefore, we examined the expression of Ang receptors in nuclei isolated from the kidneys of young adult (1.5 years) and older adult (3.0 to 5.0 years) sheep. Binding studies in renal nuclei revealed the AT(2)R as the predominant receptor subtype ( approximately 80%) in young sheep, with the Ang-(1-7) (AT(7)R; Mas protein) and AT(1)R antagonists competing for the remaining sites. Conversely, in older sheep, the AT(1)R accounted for approximately 85% of nuclear sites, whereas the Ang type 2 receptor and AT(7)R subtypes comprise approximately 20% of remaining sites. Ang II increased nuclear ROS to a greater extent in older (97+/-22%; n=6) versus young animals (7+/-2%; P=0.01; n=4), and this was abolished by an AT(1)R antagonist. The AT(7)R antagonist D-Ala(7)-Ang-(1-7) increased ROS formation to Ang II by approximately 2-fold (174+/-5% versus 97+/-22%; P<0.05) in older adults. Immunoblots of renal nuclei revealed protein bands for the AT(7)R and Ang-converting enzyme 2 (ACE2), which metabolizes Ang II to Ang-(1-7). The ACE2 inhibitor MLN4760 also exacerbated the Ang II-dependent formation of ROS (156+/-15%) and abolished the generation of Ang-(1-7) from Ang II. We conclude that an ACE2-Ang-(1-7)-AT(7)R pathway modulates Ang II-dependent ROS formation within the nucleus, providing a unique protective mechanism against oxidative stress and cell damage.
血管紧张素（Ang）1 型受体（AT(1)R）在肾核高度表达，并刺激活性氧（ROS）。目前尚不清楚 Ang 系统的其他功能成分是否调节 Ang II-AT(1)R ROS 途径。因此，我们检查了年轻成年（1.5 岁）和老年（3.0 至 5.0 岁）绵羊肾脏分离的核中 Ang 受体的表达。肾核中的结合研究表明，在年轻绵羊中，AT(2)R 是主要的受体亚型（约 80%），Ang-(1-7)（AT(7)R；Mas 蛋白）和 AT(1)R 拮抗剂竞争剩余的部位。相反，在老年绵羊中，AT(1)R 约占核部位的 85%，而 Ang 型 2 受体和 AT(7)R 亚型约占剩余部位的 20%。Ang II 增加核 ROS 的程度在老年（97+/-22%；n=6）与年轻动物（7+/-2%；P=0.01；n=4）相比更大，这一作用被 AT(1)R 拮抗剂所阻断。AT(7)R 拮抗剂 D-Ala(7)-Ang-(1-7)使 Ang II 引起的 ROS 形成增加约 2 倍（174+/-5%对 97+/-22%；P<0.05）在老年成年人中。肾核的免疫印迹显示 AT(7)R 和血管紧张素转换酶 2（ACE2）的蛋白带，ACE2 将 Ang II 代谢为 Ang-(1-7)。ACE2 抑制剂 MLN4760 也加重了 Ang II 依赖性 ROS 形成（156+/-15%），并消除了 Ang II 生成 Ang-(1-7)。我们得出结论，ACE2-Ang-(1-7)-AT(7)R 途径调节核内 Ang II 依赖性 ROS 形成，为对抗氧化应激和细胞损伤提供了独特的保护机制。
