Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2016-12, Vol.68 (6), p.1385-1392
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Biomarkers - metabolism; Disease Models, Animal; Gene Deletion; Gene Expression Regulation; Hypertension - drug therapy; Hypertension - genetics; Hypertension - physiopathology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Paraventricular Hypothalamic Nucleus - metabolism; Paraventricular Hypothalamic Nucleus - physiopathology; Protein Isoforms - metabolism; Random Allocation; Renin - genetics; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - genetics; Sensitivity and Specificity
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.116.08242

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.