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Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension. Hypertension 2016 12;68(6):1385-1392

Date

10/19/2016

Pubmed ID

27754863

Pubmed Central ID

PMC5159235

DOI

10.1161/HYPERTENSIONAHA.116.08242

Scopus ID

2-s2.0-84991696091   31 Citations

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.

Author List

Shinohara K, Liu X, Morgan DA, Davis DR, Sequeira-Lopez ML, Cassell MD, Grobe JL, Rahmouni K, Sigmund CD

Authors

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Curt 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 Variance
Angiotensin-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