Angiotensin II (Ang II) acts via neuronal Ang II type 1 receptors (AT1-R) within the brain to increase sympathetic outflow and blood pressure, and hyperactivity of these effects plays a major role in hypertension. Thus, factors that regulate the neuronal actions of Ang II in the brain will modify the effects of this peptide on blood pressure. The current proposal focuses on the role of macrophage migration inhibitory factor (MIF) as a possible intracellular regulator of these neuronal actions of Ang II, in particular at the paraventricular nucleus (PVN), a center for control of sympathetic outflow and blood pressure. Based on preliminary findings we have developed the novel hypothesis that MIF, produced within neurons in response to Ang II, acts as a chronic intracellular negative feedback regulator of Ang II's chronotropic actions. Specifically, the proposal is that: (i) In normotensive rat neurons MIF, produced in response to Ang II, exerts an inhibitory influence which dampens or prevents further stimulatory actions of Ang II on neuronal firing; (ii) MIF inhibits the neuronal chronotropic action of Ang II via it's thiol-oxidoreductase activity, scavenging of reactive oxygen species (ROS) and modulation of membrane K+ and Ca2+ currents; (iii) In normotensive rat PVN, Ang ll-induced increases in MIF expression serve to blunt or depress subsequent increases in sympathetic outflow and blood pressure elicited by Ang II. In this proposal our overall goal is to investigate a novel role of MIF as an inhibitor of Ang ll-induced responses in neurons. The above hypotheses will be tested through in vitro and in vivo studies that will combine cellular, molecular, gene transfer and physiological approaches.
The specific aims are: (1) Investigate the role of MIF as an inhibitor of the chronotropic action of Ang II in neurons; (2) Investigate the intracellular mechanisms by which MIF affects the neuronal chronotropic actions of Ang II; (3) Determine the consequences of increased MIF expression in the PVN to Ang ll-induced cardiovascular effects. These studies will establish a role for MIF as an inhibitory regulator of the CNS actions of Ang II on sympathetic outflow and blood pressure, and will lay the groundwork for determining whether a lack of this MIF regulatory mechanism contributes to hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076803-02
Application #
7102601
Study Section
Special Emphasis Panel (ZRG1-CVS-B (03))
Program Officer
Rabadan-Diehl, Cristina
Project Start
2005-08-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$497,062
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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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
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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
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Shi, Peng; Grobe, Justin L; Desland, Fiona A et al. (2014) Direct pro-inflammatory effects of prorenin on microglia. PLoS One 9:e92937
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

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