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.
N1 - Funding Information:
This work was supported through research grants from the National Institutes of Health to C.D.S. (HL084207, HL048058, HL062984, and HL125603), K.R. (HL084207), J.L.G. (HL098276), M.L.S.S.-L. (DK091330, DK096373), and grants from the American Heart Association to C.D.S. (15SFRN23480000) and K.R. (14EIA18860041), and the University of Iowa Fraternal Order of Eagles Diabetes Research Center to K.R. and J.L.G.
Publisher Copyright:
© 2016 American Heart Association, Inc.
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.
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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 -