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

Keisuke Shinohara; Xuebo Liu; Donald A Morgan; Deborah R Davis; Maria Luisa S Sequeira-Lopez; Martin D Cassell; Justin L Grobe; Kamal Rahmouni; Curt D Sigmund

doi:10.1161/HYPERTENSIONAHA.116.08242

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

Journal article

Open access

Peer reviewed

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

Keisuke Shinohara, Xuebo Liu, Donald A Morgan, Deborah R Davis, Maria Luisa S Sequeira-Lopez, Martin D Cassell, Justin L Grobe, Kamal Rahmouni and Curt D Sigmund

Hypertension (Dallas, Tex. 1979), Vol.68(6), pp.1385-1392

12/2016

DOI: 10.1161/HYPERTENSIONAHA.116.08242

PMCID: PMC5159235

PMID: 27754863

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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.

Biomarkers - metabolism

Mice, Inbred C57BL

Gene Expression Regulation

Hypertension - drug therapy

Male

Mice, Transgenic

Renin-Angiotensin System - genetics

Random Allocation

Hypertension - physiopathology

Paraventricular Hypothalamic Nucleus - physiopathology

Renin - genetics

Animals

Protein Isoforms - metabolism

Analysis of Variance

Gene Deletion

Sensitivity and Specificity

Paraventricular Hypothalamic Nucleus - metabolism

Renin-Angiotensin System - drug effects

Angiotensin-Converting Enzyme Inhibitors - pharmacology

Mice

Hypertension - genetics

Disease Models, Animal

Details

Title: Subtitle: Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension
Creators: Keisuke Shinohara - 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
Xuebo Liu - 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
Donald A Morgan - 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
Deborah R Davis - 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
Maria Luisa S Sequeira-Lopez - 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
Martin D Cassell - 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
Justin L Grobe - 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
Kamal Rahmouni - 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
Curt D Sigmund - 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. curt-sigmund@uiowa.edu
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.68(6), pp.1385-1392
Publisher: United States
DOI: 10.1161/HYPERTENSIONAHA.116.08242
PMID: 27754863
PMCID: PMC5159235
ISSN: 0194-911X
eISSN: 1524-4563
Grant note: R01 HL125603 / NHLBI NIH HHS R00 HL098276 / NHLBI NIH HHS R01 DK091330 / NIDDK NIH HHS P50 DK096373 / NIDDK NIH HHS R01 HL131689 / NHLBI NIH HHS R01 HL048058 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS R37 HL048058 / NHLBI NIH HHS K99 HL098276 / NHLBI NIH HHS
Language: English
Date published: 12/2016
Academic Unit: Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040356202771

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