Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension
Year: 2016
Type: article
Abstract: 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.
Source: Hypertension
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: ROLE OF ENHANCERS REGULATING RENIN GENE EXPRESSION, Central Renin-Angiotensin System: Metabolism, Fluid Balance, and Hypertension, Development of the Renal Arterioles, PPG - Mechanisms of Cardiovascular Protection and Disease, Hypertension: Role of Smooth Muscle Cullin-3 and the CRL3 Complex, Role of Enhancers Regulating Renin Gene Expression, Genetic and Signaling Mechanisms in the Central Regulation of Blood, Role of PPARG the PPARG Target Gene RBP7 in the Endothelium, Central Renin-Angiotensin System: Metabolism, Fluid Balance, and Hypertension, Regulation of Cell Fate during Kidney Development and Disease
OpenAlex ID: W2535804900