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.
authors.affiliation: 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.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shinohara
authors.affiliation: 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.
authors.forename: Xuebo
authors.initials: X
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.affiliation: 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.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Davis
authors.affiliation: 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.
authors.forename: Maria Luisa S
authors.initials: ML
authors.lastname: Sequeira-Lopez
authors.affiliation: 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.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Cassell
authors.affiliation: 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.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.affiliation: 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.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.affiliation: 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.
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism* / Q000503:physiopathology; D020033:Protein Isoforms / Q000378:metabolism; D011897:Random Allocation; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics*; D012680:Sensitivity and Specificity
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D020033:Protein Isoforms; D012083:Renin
keywords: angiotensin II; brain; hypertension; renin; sympathetic nervous system