Shinohara Keisuke, Liu Xuebo, Morgan Donald A, Davis Deborah R, Sequeira-Lopez Maria Luisa S, Cassell Martin D, Grobe Justin L, Rahmouni Kamal, Sigmund Curt D
From the Department of Pharmacology (K.S., X.L., D.A.M., D.R.D., J.L.G., K.R., C.D.S.), Department of Anatomy and Cell Biology (M.D.C.), and UIHC Center for Hypertension Research (J.L.G., K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Pediatrics (M.L.S.S.-L.), University of Virginia, Charlottesville.
Hypertension. 2016 Dec;68(6):1385-1392. doi: 10.1161/HYPERTENSIONAHA.116.08242. Epub 2016 Oct 17.
The renin-angiotensin system (RAS) in the brain is a critical determinant of blood pressure, but the mechanisms regulating RAS activity in the brain remain unclear. Expression of brain renin (renin-b) occurs from an alternative promoter-first exon. The predicted translation product is a nonsecreted enzymatically active renin whose function is unknown. We generated a unique mouse model by selectively ablating the brain-specific isoform of renin (renin-b) while preserving the expression and function of the classical isoform expressed in the kidney (renin-a). Preservation of renal renin was confirmed by measurements of renin gene expression and immunohistochemistry. Surprisingly, renin-b-deficient mice exhibited hypertension, increased sympathetic nerve activity to the kidney and heart, and impaired baroreflex sensitivity. Whereas these mice displayed decreased circulating RAS activity, there was a paradoxical increase in brain RAS activity. Physiologically, renin-b-deficient mice exhibited an exaggerated depressor response to intracerebroventricular administration of losartan, captopril, or aliskiren. At the molecular level, renin-b-deficient mice exhibited increased expression of angiotensin-II type 1 receptor in the paraventricular nucleus, which correlated with an increased renal sympathetic nerve response to leptin, which was dependent on angiotensin-II type 1 receptor activity. Interestingly, despite an ablation of renin-b expression, expression of renin-a was significantly increased in rostral ventrolateral medulla. These data support a new paradigm for the genetic control of RAS activity in the brain by a coordinated regulation of the renin isoforms, with expression of renin-b tonically inhibiting expression of renin-a under baseline conditions. Impairment of this control mechanism causes neurogenic hypertension.
大脑中的肾素-血管紧张素系统（RAS）是血压的关键决定因素，但调节大脑中RAS活性的机制仍不清楚。脑肾素（肾素-b）的表达来自一个替代启动子-第一外显子。预测的翻译产物是一种非分泌型的具有酶活性的肾素，其功能尚不清楚。我们通过选择性切除肾素的脑特异性异构体（肾素-b），同时保留肾脏中表达的经典异构体（肾素-a）的表达和功能，构建了一个独特的小鼠模型。通过肾素基因表达测量和免疫组织化学证实了肾脏肾素的保留。令人惊讶的是，肾素-b缺陷小鼠表现出高血压、对肾脏和心脏的交感神经活动增加以及压力反射敏感性受损。虽然这些小鼠循环RAS活性降低，但大脑RAS活性却出现了自相矛盾的增加。在生理上，肾素-b缺陷小鼠对脑室内注射氯沙坦、卡托普利或阿利吉仑表现出夸张的降压反应。在分子水平上，肾素-b缺陷小鼠室旁核中血管紧张素II 1型受体的表达增加，这与肾脏交感神经对瘦素的反应增加相关，而这依赖于血管紧张素II 1型受体的活性。有趣的是，尽管肾素-b的表达被切除，但延髓头端腹外侧肾素-a的表达却显著增加。这些数据支持了一种新的范式，即通过肾素异构体的协调调节对大脑中RAS活性进行基因控制，在基线条件下，肾素-b的表达可抑制肾素-a的表达。这种控制机制的损害会导致神经源性高血压。
