Hypertension is an epidemic health concern and a major risk factor for cardiovascular disease, the leading cause of death in the U.S. Many forms of hypertension are of neurogenic origin;however, the neural mechanism(s) underlying the development and progression of neurogenic hypertension are incompletely understood. Angiotensin-II (Ang-II), the effector peptide of the renin-angiotensin system, is a potent mediator of cardiovascular function that has pleiotropic actions within the brain. Ang-II is known to induce inflammation via the activation of the angiotensin type 1a receptor (AT1a) in a number of peripheral tissues and in the brain and this is thought to contribute to its hypertensive actions. Consistent with this, hypertension, in addition to being accompanied by enhanced renin-angiotensin system activity is also associated with a mild inflammatory state. One critical site of Ang-II actions within the brain is the paraventricular nucleus of the hypothalamus (PVN), which densely expresses AT1a and integrates signals to and from brain regions critical for the regulation of cardiovascular function and sympathetic nerve activity. This proposal investigates the role of the PVN AT1a in the inflammatory and sympathoexcitatory actions of elevated Ang-II. The proposed experiments will test the overall hypothesis that Ang-II acts at the PVN AT1a receptor to enhance inflammation and microglial activation and that this is an important mechanism for Ang-II-induced hypertension and augmented sympathetic outflow. In the first Specific Aim, experiments will utilize the Cre/lox system in mice to test the specific hypothesis that PVN AT1a are necessary for Ang-II-induced increases in blood pressure and sympathetic nervous system activity. Angiotensin-II-induced cardiovascular dysfunction (telemetric blood pressure assessment) and neuronal activation (c-Fos immunohistochemistry) of cardiovascular control centers of the brain will be assessed in mice that lack AT1a in the PVN and controls. In the second Specific Aim, a combination of the Cre/lox system and pharmacological approaches in mice will be used to determine the role of interactions between PVN AT1a, transforming growth factor beta and inflammation in the regulation of cardiovascular function during elevated Ang-II. Specifically, the necessity of PVN AT1a and transforming growth factor beta signaling for the inflammatory and hypertensive consequences of elevated Ang-II will be assessed. Important endpoints for Aim 2 will include the assessment of proinflammatory cytokines and microglial activation within the PVN and other cardiovascular control centers, as well as the telemetric assessment of cardiovascular function. The proposed research is significant because uncovering the mechanisms of Ang-II regulation of inflammation and cardiovascular function may lead to new strategies for the treatment and prevention of neurogenic hypertension.
Although there are a number of treatment strategies for high blood pressure, less than 50% of hypertensive patients have their condition under control. The objective of the proposed research is to understand mechanisms contributing to hypertension by investigating interactions between angiotensin-II's inflammatory actions in the brain and high blood pressure. This is of particular relevance to public health because uncovering the mechanisms of Ang-II regulation of inflammation and cardiovascular function may lead to new strategies for the treatment and prevention of hypertension.
|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; Liu, Meng; Rodríguez, Vermalí 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|
|de Kloet, Annette D; Pioquinto, David J; Nguyen, Dan et al. (2014) Obesity induces neuroinflammation mediated by altered expression of the renin-angiotensin system in mouse forebrain nuclei. Physiol Behav 136:31-8|
|Smith, Justin A; Wang, Lei; Hiller, Helmut et al. (2014) Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamic-pituitary-adrenal axis in male mice. Physiol Behav 136:91-6|
|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|