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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1385-1392
Number of pages8
JournalHypertension
Volume68
Issue number6
DOIs
Publication statusPublished - Dec 1 2016

Fingerprint

Renin
Protein Isoforms
Hypertension
Brain
Renin-Angiotensin System
Kidney
Angiotensin Type 1 Receptor
Losartan
Baroreflex
Paraventricular Hypothalamic Nucleus
Captopril
Leptin
Exons

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Shinohara, K., Liu, X., Morgan, D. A., Davis, D. R., Sequeira-Lopez, M. L. S., Cassell, M. D., ... Sigmund, C. D. (2016). Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension. Hypertension, 68(6), 1385-1392. https://doi.org/10.1161/HYPERTENSIONAHA.116.08242

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

In: Hypertension, Vol. 68, No. 6, 01.12.2016, p. 1385-1392.

Research output: Contribution to journalArticle

Shinohara, K, Liu, X, Morgan, DA, Davis, DR, Sequeira-Lopez, MLS, Cassell, MD, Grobe, JL, Rahmouni, K & Sigmund, CD 2016, 'Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension', Hypertension, vol. 68, no. 6, pp. 1385-1392. https://doi.org/10.1161/HYPERTENSIONAHA.116.08242
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. / Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension. In: Hypertension. 2016 ; Vol. 68, No. 6. pp. 1385-1392.
@article{84aa4cc4ee934963a0b5e04c75a02751,
title = "Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension",
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 = "Keisuke Shinohara and Xuebo Liu and Morgan, {Donald A.} and Davis, {Deborah R.} and Sequeira-Lopez, {Maria Luisa S.} and Cassell, {Martin D.} and Grobe, {Justin L.} and Kamal Rahmouni and Sigmund, {Curt D.}",
year = "2016",
month = "12",
day = "1",
doi = "10.1161/HYPERTENSIONAHA.116.08242",
language = "English",
volume = "68",
pages = "1385--1392",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension

AU - Shinohara, Keisuke

AU - Liu, Xuebo

AU - Morgan, Donald A.

AU - Davis, Deborah R.

AU - Sequeira-Lopez, Maria Luisa S.

AU - Cassell, Martin D.

AU - Grobe, Justin L.

AU - Rahmouni, Kamal

AU - Sigmund, Curt D.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84991696091&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991696091&partnerID=8YFLogxK

U2 - 10.1161/HYPERTENSIONAHA.116.08242

DO - 10.1161/HYPERTENSIONAHA.116.08242

M3 - Article

C2 - 27754863

AN - SCOPUS:84991696091

VL - 68

SP - 1385

EP - 1392

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 6

ER -