University of Iowa Researchers identify a new fundamental mechanism which limits activity of the brain renin-angiotensin

The renin-angiotensin system (RAS) is a complex hormone system that is involved in the regulation of plasma sodium concentration and arterial blood pressure. Localized expression of RASs has been demonstrated in a variety of tissues including the cardiovascular system, kidneys and nervous system among others. In the recent study

Dr. Shinohara and Dr Sigmund at EB meeting 2015

published in the journal Hypertension, University of Iowa and University of Virginia researchers lead by Postdoctoral Fellow Dr. Keisuke Shinohara in the laboratory of senior author Dr. Curt D. Sigmund, Professor of Pharmacology, “sought to examine the role, if any, of intracellular renin in the brain” said Dr. Sigmund.  To address this question, researchers generated a new genetic mouse model by specifically deleting the brain specific isoform of renin, termed renin-b without affecting the expression or function of classical renin-a, expressed in the kidneys. To their surprise, ‘renin-b–deficient mice exhibited neurogenic hypertension and increased sympathetic nerve activity to the kidney and heart’. Further examination on the molecular level showed “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.” According to Dr. Sigmund, these findings revealed to the researchers “a new paradigm for the genetic control of renin-angiotensin system activity in the brain by a coordinated transcriptional regulation of renin isoforms.”

Author Affiliations

Roy J. Lucille A. Carver College of Medicine, University of Iowa researchers involved in the study were senior author Dr. Curt D. Sigmund, Professor of Pharmacology and the Roy J. Carver Chair in Hypertensive Research; lead author Dr. Keisuke Shinohara*, Postdoctoral Fellow; Dr. Xuebo Liu, Research Scientist; Donald A Morgan, Research Specialist; Deborah R. Davis, Research Specialist; Dr. Justin L Grobe, Assistant Professor of Pharmacology; Dr. Kamal Rahmouni, Professor of Pharmacology; from the Department of Pharmacology. Dr. Martin D Cassell, Professor of Anatomy and Cell Biology, Roy J. Lucille A. Carver College of Medicine, University of Iowa.  Dr. Maria Luisa S. Sequeira-Lopez, Harrison Distinguished Professorship in Pediatrics, Department of Pediatrics, University of Virginia.

Dr. M.Cassell , Dr. J. Grobe, Dr. K. Rahmouni and Dr. C. Sigmund are members of the UIHC Center for Hypertension Research and the Abboud Cardiovascular Research Center , University of Iowa.

*Dr. K Shinohara is currently a cardiology fellow at the Kyushu University School of Medicine.

Sources of Funding

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. We gratefully acknowledge the generous research support of the Roy J. Carver Trust.

Original Article

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 and Curt D. Sigmund. Hypertension.  2016; HYPERTENSIONAHA.116.08242

Originally published October 17, 2016

Read the full article at Hypertension

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