Abstract
Abstract 17309: Selective Deletion of Brain-specific Renin Isoform Causes Hypertension and Elevated Sympathetic Nerve Activity
Circulation (New York, N.Y.), Vol.134(Suppl_1), pp.A17309-A17309
11/11/2016
Abstract
IntroductionThe renin-angiotensin system (RAS) in the brain plays a critical role in regulating blood pressure and metabolism via sympathetic nerve activity. A dominant renin isoform in the brain (renin-b) occurs from an alternative promoter-1 exon, and is a non-secreted enzymatically active renin, whereas the classical renin isoform (renin-a) is predominantly expressed in the kidney.HypothesisBrain-specific renin isoform, renin-b, regulates blood pressure, metabolism, and sympathetic nerve activity thorough alteration of brain RAS activity.Methods and ResultsWe developed renin-b knockout (KO) mice that preserves the classical renin isoform, renin-a, expressed in the kidney. Surprisingly, renin-b KO mice exhibited hypertension (systolic BP130±2 mmHg, n=8 vs 122±2 mmHg in controls, n=7, P<0.01), increased metabolic rate (0.156±0.005 kcal/h, n=46 vs 0.145±0.003 kcal/h in controls, n=53, P<0.05), and sympathetic hyperactivity (renal sympathetic nerve activity102.7±9.9 spikes/sec, n=7 vs 62.9±1.8 spikes/sec in controls, n=5, P<0.01). Chronic ICV injection of losartan abolished the elevated blood pressure (systolic BP, 111±2 mmHg with losartan, n=6 vs 137±6 mmHg with vehicle, n=7, P<0.05) and sympathetic activity (low to high frequency ratio of heart rate variability spectra, 0.871±0.168 with losartan, n=6 vs 1.483±0.260 with vehicle, n=6, P<0.05) in renin-b KO mice. ICV injection of ACE inhibitor, captopril, and renin inhibitor, aliskiren, also normalized the elevated blood pressure in renin-b KO mice. AT1a receptor mRNA was upregulated in the paraventricular nucleus of renin-b KO mice. Interestingly, renin-a mRNA expression was increased in the brain. These data suggested that, in renin-b KO mice, the brain RAS activity was paradoxically increased through increased expression of renin-a in the brain, resulting in elevated blood pressure, metabolic rate, and sympathetic nerve activity.ConclusionThis study support a new paradigm for the genetic control of RAS activity in the brain by a coordinated regulation of the renin isoforms with renin-b tonically inhibiting expression of renin-a under baseline conditions.
Details
- Title: Subtitle
- Abstract 17309: Selective Deletion of Brain-specific Renin Isoform Causes Hypertension and Elevated Sympathetic Nerve Activity
- Creators
- Keisuke Shinohara - Pharmacology, Univ of Iowa, Iowa City, IAXuebo LiuDonald MorganJustin GrobeKamal RahmouniCurt Sigmund
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.134(Suppl_1), pp.A17309-A17309
- Publisher
- by the American College of Cardiology Foundation and the American Heart Association, Inc
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/11/2016
- Academic Unit
- Molecular Physiology and Biophysics; Neuroscience and Pharmacology; Internal Medicine; Iowa Neuroscience Institute
- Record Identifier
- 9984071952802771
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