From the Division of Vascular Medicine and Pharmacology, Department of Internal Medicine (B.S.v.T., A.G.M., L.t.R., D.S., E.U., I.M.G., F.P.J.L., A.H.J.D.), Department of Vascular Surgery (B.S.v.T., L.t.R., I.v.d.P., J.E.), Department of Molecular Genetics, Cancer Genomics Center Netherlands (B.S.v.T., I.v.d.P., J.E.), Division of Nephrology and Transplantation, Department of Internal Medicine (D.S., E.U.), Department of Radiation Oncology (J.E.), Erasmus MC, Rotterdam, The Netherlands; Department of Molecular Cardiovascular Endocrinology, Max Delbrück Center, Berlin, Germany (F.Q., N.A., M.B.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Germany (N.A., M.B.); Berlin Institute of Health (BIH), Germany (M.B.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Germany (M.B.); Institute of Pathophysiology, Faculty of Medicine, Comenius University (L.P., R.R.); Institute of Normal and Pathophysiological Physiology, Slovak Academy of Sciences, Bratislava, Slovak Republic (L.P.); and Attoquant Diagnostics (O.D., M.P.) and Department of Internal Medicine III (O.D.), Medical University of Vienna, Austria.
Hypertension. 2017 Jun;69(6):1136-1144. doi: 10.1161/HYPERTENSIONAHA.116.08922. Epub 2017 Apr 10.
Because of the presence of the blood-brain barrier, brain renin-angiotensin system activity should depend on local (pro)renin synthesis. Indeed, an intracellular form of renin has been described in the brain, but whether it displays angiotensin (Ang) I-generating activity (AGA) is unknown. Here, we quantified brain (pro)renin, before and after buffer perfusion of the brain, in wild-type mice, renin knockout mice, deoxycorticosterone acetate salt-treated mice, and Ang II-infused mice. Brain regions were homogenized and incubated with excess angiotensinogen to detect AGA, before and after prorenin activation, using a renin inhibitor to correct for nonrenin-mediated AGA. Renin-dependent AGA was readily detectable in brain regions, the highest AGA being present in brain stem (>thalamus=cerebellum=striatum=midbrain>hippocampus=cortex). Brain AGA increased marginally after prorenin activation, suggesting that brain prorenin is low. Buffer perfusion reduced AGA in all brain areas by >60%. Plasma renin (per mL) was 40× to 800× higher than brain renin (per gram). Renin was undetectable in plasma and brain of renin knockout mice. Deoxycorticosterone acetate salt and Ang II suppressed plasma renin and brain renin in parallel, without upregulating brain prorenin. Finally, Ang I was undetectable in brains of spontaneously hypertensive rats, while their brain/plasma Ang II concentration ratio decreased by 80% after Ang II type 1 receptor blockade. In conclusion, brain renin levels (per gram) correspond with the amount of renin present in 1 to 20 μL of plasma. Brain renin disappears after buffer perfusion and varies in association with plasma renin. This indicates that brain renin represents trapped plasma renin. Brain Ang II represents Ang II taken up from blood rather than locally synthesized Ang II.
由于血脑屏障的存在，大脑肾素-血管紧张素系统的活性应该依赖于局部（前）肾素的合成。事实上，已经在大脑中描述了一种细胞内形式的肾素，但它是否具有血管紧张素（Ang）I 生成活性（AGA）尚不清楚。在这里，我们在野生型小鼠、肾素敲除小鼠、去氧皮质酮盐处理小鼠和 Ang II 输注小鼠中，定量了脑（前）肾素，在脑缓冲液灌注前后。用肾素抑制剂校正非肾素介导的 AGA 后，将脑区匀浆并与过量血管紧张素原孵育，以检测 AGA，在激活前肾素之前和之后。脑区很容易检测到肾素依赖性 AGA，脑干中 AGA 最高（>丘脑=小脑=纹状体=中脑>海马=皮质）。前肾素激活后，脑 AGA 略有增加，表明脑前肾素水平较低。缓冲液灌注使所有脑区的 AGA 降低了>60%。每毫升血浆肾素（per mL）比每克脑肾素（per gram）高 40 到 800 倍。肾素敲除小鼠的血浆和脑中均无法检测到肾素。去氧皮质酮盐和 Ang II 平行抑制血浆肾素和脑肾素，而不上调脑前肾素。最后，自发性高血压大鼠的脑中无法检测到 Ang I，而它们的脑/血浆 Ang II 浓度比在 Ang II 型 1 受体阻断后降低了 80%。总之，脑肾素水平（每克）与 1 到 20 μL 血浆中存在的肾素量相对应。缓冲液灌注后脑肾素消失，与血浆肾素变化相关。这表明脑肾素代表被困的血浆肾素。脑 Ang II 代表从血液中摄取的 Ang II，而不是局部合成的 Ang II。
