Abstract 17309: Selective Deletion of Brain-specific Renin Isoform Causes Hypertension and Elevated Sympathetic Nerve Activity
Introduction: The 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-1st exon, and is a non-secreted enzymatically active renin, whereas the classical renin isoform (renin-a) is predominantly expressed in the kidney.
Hypothesis: Brain-specific renin isoform, renin-b, regulates blood pressure, metabolism, and sympathetic nerve activity thorough alteration of brain RAS activity.
Methods and Results: We 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 BP: 130±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 activity: 102.7±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.
Conclusion: This 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.
Author Disclosures: K. Shinohara: None. X. Liu: None. D.A. Morgan: None. J.L. Grobe: None. K. Rahmouni: None. C.D. Sigmund: None.
- © 2016 by American Heart Association, Inc.