Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension. Hypertension 2016 Dec;68(6):1385-1392
Date
10/19/2016Pubmed ID
27754863Pubmed Central ID
PMC5159235DOI
10.1161/HYPERTENSIONAHA.116.08242Scopus ID
2-s2.0-84991696091 (requires institutional sign-in at Scopus site) 42 CitationsAbstract
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.
Author List
Shinohara K, Liu X, Morgan DA, Davis DR, Sequeira-Lopez ML, Cassell MD, Grobe JL, Rahmouni K, Sigmund CDAuthors
Justin L. Grobe PhD Professor in the Physiology department at Medical College of WisconsinCurt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Analysis of VarianceAngiotensin-Converting Enzyme Inhibitors
Animals
Biomarkers
Disease Models, Animal
Gene Deletion
Gene Expression Regulation
Hypertension
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Paraventricular Hypothalamic Nucleus
Protein Isoforms
Random Allocation
Renin
Renin-Angiotensin System
Sensitivity and Specificity
