Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
Clin Sci (Lond). 2021 Jan 29;135(2):259-274. doi: 10.1042/CS20201239.
Brain renin-angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6-8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 ± 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (<6 fmol/g). Gene silencing of liver angiotensinogen using siRNA lowered circulating angiotensinogen by 97 ± 0.3%, and made brainstem angiotensin II undetectable in all rats (P<0.05 vs. non-DOCA-salt), although brainstem angiotensinogen remained intact. As expected for this model, neither siRNA nor valsartan attenuated the hypertensive response to DOCA-salt, whereas spironolactone normalized blood pressure and restored brain angiotensin II together with circulating renin and angiotensin II. In conclusion, despite local synthesis of angiotensinogen in the brain, brain angiotensin II depended on circulating angiotensinogen. That DOCA-salt suppressed circulating and brain angiotensin II in parallel, while spironolactone simultaneously increased brain angiotensin II and lowered blood pressure, indicates that DOCA-salt hypertension is not mediated by brain RAS activation.
脑肾素-血管紧张素系统（RAS）的激活被认为介导了脱氧皮质酮醋酸盐（DOCA）-盐高血压，这是人类原发性醛固酮增多症的动物模型。在这里，我们确定了脑干部位的血管紧张素 II 是否由局部合成的血管紧张素原产生，并介导了 DOCA-盐高血压。为此，我们用肝靶向的血管紧张素原 siRNA、血管紧张素 II 型 1 受体拮抗剂缬沙坦或盐皮质激素受体拮抗剂螺内酯对慢性 DOCA-盐高血压大鼠进行治疗（每组 n = 6-8）。我们通过酶动力学测定来量化循环中的血管紧张素原和肾素，通过 Western blot 来量化组织中的血管紧张素原，通过 LC-MS/MS 来量化血管紧张素代谢物。在没有 DOCA-盐的大鼠中，所有大鼠都检测到循环血管紧张素 II，而 7 只大鼠中有 5 只检测到脑干部位血管紧张素 II。DOCA-盐使平均动脉压升高 19 ± 1 mmHg，并使循环中的肾素和血管紧张素 II 降低超过 90%，而 7 只大鼠中有 5 只大鼠的脑干部位血管紧张素 II 无法检测到（<6 fmol/g）。使用 siRNA 对肝血管紧张素原进行基因沉默使循环中的血管紧张素原降低了 97 ± 0.3%，并使所有大鼠的脑干部位血管紧张素 II 无法检测到（与非 DOCA-盐相比，P<0.05），尽管脑干部位的血管紧张素原仍然完整。与该模型一致，siRNA 或缬沙坦均未减轻 DOCA-盐引起的高血压反应，而螺内酯则使血压正常化并恢复了循环中的肾素、血管紧张素 II 和脑内的血管紧张素 II。总之，尽管脑内局部合成了血管紧张素原，但脑内的血管紧张素 II 依赖于循环中的血管紧张素原。DOCA-盐使循环和脑内血管紧张素 II 同时受到抑制，而螺内酯同时增加脑内血管紧张素 II 并降低血压，这表明 DOCA-盐高血压不是由脑 RAS 激活介导的。
