Hypertension affects approximately 50 million Americans and progression of this disease significantly increases risk for cardiovascular disease. Recent clinical studies demonstrate, that hypertension also is associated with mental health disorders. Specifically, hypertension increases the risk of anxiety disorders, and inversely, anxiety disorders predict the risk and severity of hypertension and cardiovascular disease. While the onset of hypertension is attributed to over activity of the renin-angiotensin-system (RAS), the development of anxiety is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The effector peptide of the RAS, angiotensin II (ANGII), exerts the majority of its biological effects via activation of angiotensin type 1 receptors (ATI R). Interestingly, ATI R are expressed throughout the HPA axis and emerging evidence has implicated ANGII as an important mediator of the stress response. Chronic exposure to stress up-regulates the HPA axis and RAS, thereby negatively affecting cardiovascular and mental health. Given that chronic stress similarly up-regulates the HPA axis and the RAS, it is likely that an interaction between these systems underlies the effects that chronic stress has on mental health and cardiovascular function. In this regard, our recent study found that circulating ANGII drives activation of the HPA axis by stimulating AT1R in the subfornical, a specialized forebrain structure that binds blood-borne hormones. Because repeated stress increases ATI R expression in the subfornical organ, it is likely that chronic stress potentiates the influence of circulating ANGII on the HPA axis, thereby inducing cardiovascular and affective disorders. Collectively, these studies suggest that therapies targeting the RAS may influence the onset of brain-based disorders like anxiety, and therefore, it is important to understand the central angiotensinergic pathways that influence responses to stress. Accordingly, the proposed experiments will utilize antisense oligodeoxynucleotides to inhibit AT1R expression in the subfornical organ of laboratory rats to determine the contribution of these receptors to the cardiovascular, HPA and behavioral responses to acute and chronic exposure to stress. These studies are designed to test the overall hypothesis that inhibition of AT1R in the subfornical organ will limit stress responding and alleviate the deleterious consequences of chronic stress exposure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
1K99HL096830-01
Application #
7707282
Study Section
Special Emphasis Panel (ZHL1-CSR-Z (M3))
Program Officer
Commarato, Michael
Project Start
2009-09-15
Project End
2011-07-31
Budget Start
2009-09-15
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$122,610
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
de Kloet, Annette D; Pitra, Soledad; Wang, Lei et al. (2016) Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice. Endocrinology 157:3167-80
de Kloet, Annette D; Wang, Lei; Ludin, Jacob A et al. (2016) Reporter mouse strain provides a novel look at angiotensin type-2 receptor distribution in the central nervous system. Brain Struct Funct 221:891-912
Wang, Lei; de Kloet, Annette D; Pati, Dipanwita et al. (2016) Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors. Neuropharmacology 105:114-123
de Kloet, Annette D; Krause, Eric G; Solomon, Matia B et al. (2015) Adipocyte glucocorticoid receptors mediate fat-to-brain signaling. Psychoneuroendocrinology 56:110-9
de Kloet, Annette D; Liu, Meng; RodrĂ­guez, VermalĂ­ et al. (2015) Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control. Am J Physiol Regul Integr Comp Physiol 309:R444-58
Sumners, Colin; de Kloet, Annette D; Krause, Eric G et al. (2015) Angiotensin type 2 receptors: blood pressure regulation and end organ damage. Curr Opin Pharmacol 21:115-21
Frazier, Charles J; Pati, Dipanwita; Hiller, Helmut et al. (2013) Acute hypernatremia exerts an inhibitory oxytocinergic tone that is associated with anxiolytic mood in male rats. Endocrinology 154:2457-67
de Kloet, Annette D; Pati, Dipanwita; Wang, Lei et al. (2013) Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity. J Neurosci 33:4825-33
Krause, Eric G; de Kloet, Annette D; Flak, Jonathan N et al. (2011) Hydration state controls stress responsiveness and social behavior. J Neurosci 31:5470-6
Krause, Eric G; de Kloet, Annette D; Scott, Karen A et al. (2011) Blood-borne angiotensin II acts in the brain to influence behavioral and endocrine responses to psychogenic stress. J Neurosci 31:15009-15

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