The sympathetic nervous system and angiotensin II (ANG) are implicated in obesity-induced hypertension (HT), but the mechanisms are poorly defined. Our preliminary data support a role for brain ANG signaling in increased arterial pressure (AP) in diet-induced obese (DIO) mice. Additional data reveal striking endoplasmic reticulum (ER) stress in key brain cardiovascular control regions (SFO-PVN axis) in DIO and indicate that chemical manipulation of ER stress influences sympathetic nerve activity (SNA) and AP in this model. Our data also demonstrate that DIO causes oxidative stress in the SFO-PVN axis and this is linked to ER stress. Furthermore, new preliminary data show that both ER stress and oxidative stress in this brain axis are coupled to leptin signaling in DIO mice. Additional new data raise the possibility that DIO-mediated oxidative and ER stress in the brain modulate the facilitatory effect of brain ANG on energy expenditure (EE). Based on these promising, multifaceted preliminary data, we will address four innovative and interrelated concepts: 1) dissociation between central mechanisms controlling energy homeostasis and cardiovascular responses in obesity-HT;2) brain ER stress, a new disease paradigm, as a key underlying mechanism;3) the role of redox signaling, with potential links to ER stress pathways, in obesity-HT and 4) the SFO-PVN axis as a major player in DIO-mediated cardiovascular and metabolic dysregulation. We will address the overall hypothesis that in DIO mice, increased brain ANG and/or leptin signaling promotes ER stress and oxidant stress in the SFO-PVN axis. We postulate that this ER/oxidant stress contributes to the increased renal SNA and AP in DIO mice, but conversely acts in the SFO-PVN axis to blunt or reverse brain ANG- and/or leptin-mediated facilitatory effects on thermogenic SNA and EE in this model of obesity-HTN. To address this innovative hypothesis, we have assembled multiple sophisticated research tools, including 1) genetically engineered mouse models and viral vectors that allow brain site-selective targeting of key ANG, oxidant and ER stress molecules;2) state-of-the-art assays for visualizing and quantifying ER stress;3) sophisticated integrative physiology for evaluating AP, SNA and EE. A notable strength ofthe project is the extensive interfacing, both conceptual and technical, with Projects 2 and 3.

Public Health Relevance

Obesity-induced HT is a major global health problem that involves the sympathetic nervous system. This research has the potential to advance understanding of fundamental molecular and physiologic mechanisms by which the brain triggers sympathetic activation and HT in obesity, and could have implications for novel therapies targeting the neurogenic component of obesity-induced HT and its cardiovascular complications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL084207-06A1
Application #
8524229
Study Section
Special Emphasis Panel (ZHL1-PPG-J (F1))
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$502,972
Indirect Cost
$28,370
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Contreras, Cristina; González-García, Ismael; Martínez-Sánchez, Noelia et al. (2014) Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep 9:366-77
Borges, Giulianna R; Morgan, Donald A; Ketsawatsomkron, Pimonrat et al. (2014) Interference with peroxisome proliferator-activated receptor-? in vascular smooth muscle causes baroreflex impairment and autonomic dysfunction. Hypertension 64:590-6
Li, Wencheng; Peng, Hua; Mehaffey, Eamonn P et al. (2014) Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension. Hypertension 63:316-23
Rahmouni, Kamal (2014) Obesity-associated hypertension: recent progress in deciphering the pathogenesis. Hypertension 64:215-21
Sones, Jenny L; Lob, Heinrich E; Isroff, Catherine E et al. (2014) Role of decidual natural killer cells, interleukin-15, and interferon-? in placental development and preeclampsia. Am J Physiol Regul Integr Comp Physiol 307:R490-2
Coble, Jeffrey P; Johnson, Ralph F; Cassell, Martin D et al. (2014) Activity of protein kinase C-? within the subfornical organ is necessary for fluid intake in response to brain angiotensin. Hypertension 64:141-8
Ramkumar, Nirupama; Stuart, Deborah; Rees, Sara et al. (2014) Collecting duct-specific knockout of renin attenuates angiotensin II-induced hypertension. Am J Physiol Renal Physiol 307:F931-8
Owen, Bryn M; Ding, Xunshan; Morgan, Donald A et al. (2014) FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 20:670-7
Grobe, Justin L; Sigmund, Curt D (2014) Another reason to eat your greens: cardiopulmonary protection by dietary delivery of angiotensin-converting enzyme-2 and angiotensin-(1-7) made in plants. Hypertension 64:1182-3
Shi, Peng; Grobe, Justin L; Desland, Fiona A et al. (2014) Direct pro-inflammatory effects of prorenin on microglia. PLoS One 9:e92937

Showing the most recent 10 out of 81 publications