Program Director/Principal Investigator (Last, First, Middle): Sigmund, Curt D. PROJECT SUMMARY (See instnjctions): The renin-angiotensin system is a major regulator of blood pressure and electrolyte balance in animals and humans and has been implicated in the genetic basis of essential hypertension. Renin is the rate limiting enzyme cascade and its synthesis is highly regulated at both the transcriptional, post-transcriptional and secretory level. Our efforts ofthe past 15 years have lead to significant advances in our understanding of the transcriptional mechanisms regulating this important gene and have begun coupling transcription to physiology. With the development of new innovative technologies for interrogation of individual genes and proteins in both cells and whole animals, we are now poised for the first time to make important discoveries linking transcriptional events to specific physiological responses and pathways. Studies in the l /IERIT EXTENSION period will continue to focus on the overall hypothesis: The enhancers found upstream ofthe renin gene along with their cognate transcription factors (and specific ligands), co-activators, and co- repressors play a major role in controlling the cell- and tissue-specificity of expression and the transcriptional responses to physiological cues. We will build upon the progress and major scientific achievements ofthe current budget period to dramatically expand our knowledge on the regulation of renin gene expression by: 1) examining the relevance and role of CREB/ATF and HoxDIO transcription factors on the mechanisms of renin expression in renin expressing cells both in vitro and in vivo;2) examining cellular and transcriptional mechanisms regulating renin gene by oxidative stress;3) identifying the function of conserved non-coding sequences upstream ofthe kidney enhancer using cell lines and recombineering followed by BAC-mediated transgenesis;4) assessing the novel role of micro RNAs (miRNAs) in the regulation of renin in vitro and in vivo;and 5) examining the importance of brain renin in the regulation of hydromineral balance and energy metabolism.

Public Health Relevance

Renin is the first and rate limiting step in the production of angiotensin peptides which have pleiotropic effects on blood pressure, sodium and water homeostasis, sympathetic nervous system and systemic metabolism. These studies will link transcriptional signals regulating the renin gene with physiological endpoints controlling blood pressure and metabolism which may go awry in hypertension. I

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL048058-19
Application #
8212154
Study Section
Special Emphasis Panel (NSS)
Program Officer
Maric-Bilkan, Christine
Project Start
1993-01-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
19
Fiscal Year
2012
Total Cost
$476,789
Indirect Cost
$161,035
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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
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
De Silva, T Michael; Modrick, Mary L; Ketsawatsomkron, Pimonrat et al. (2014) Role of peroxisome proliferator-activated receptor-? in vascular muscle in the cerebral circulation. Hypertension 64:1088-93
Coble, Jeffrey P; Cassell, Martin D; Davis, Deborah R et al. (2014) Activation of the renin-angiotensin system, specifically in the subfornical organ is sufficient to induce fluid intake. Am J Physiol Regul Integr Comp Physiol 307:R376-86
Carrillo-Sepulveda, Maria Alicia; Keen, Henry L; Davis, Deborah R et al. (2014) Role of vascular smooth muscle PPAR? in regulating AT1 receptor signaling and angiotensin II-dependent hypertension. PLoS One 9:e103786
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
Sigmund, Curt D (2013) A clinical link between peroxisome proliferator-activated receptor ýý and the renin-angiotensin system. Arterioscler Thromb Vasc Biol 33:676-8
Grobe, Justin L; Rahmouni, Kamal; Liu, Xuebo et al. (2013) Metabolic rate regulation by the renin-angiotensin system: brain vs. body. Pflugers Arch 465:167-75
Park, Sungmi; Lu, Ko-Ting; Liu, Xuebo et al. (2013) Allele-specific expression of angiotensinogen in human subcutaneous adipose tissue. Hypertension 62:41-7

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