The renin-angiotensin system (RAS) is a major regulator of blood pressure and electrolyte balance in animals and humans. Renin is the rate limiting enzyme of the RAS cascade and its synthesis is highly regulated at both the transcriptional, post-transcriptional and secretory level. Despite years of investigation, our understanding of the mechanisms regulating renin gene expression remained very incomplete. The purpose of this proposal therefore is to test the overall hypothesis that the enhancers found upstream of the 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. To test and expand upon this hypothesis we have developed the following three main specific aims: 1) test the hypothesis that individual transcription factors identified to bind to the renin enhancer are important modulators of renin promoter/enhancer activity and endogenous renin expression at baseline, and under conditions where renin expression is either stimulated or repressed, 2) test the hypothesis that two enhancers of transcription, the kidney enhancer (KE) and chorionic enhancer (CE) in the human renin 5'flanking region are essential elements controlling tissue- and cell- specific expression and the responses to physiological cues, and 3) test the hypothesis that the transcription factors Ear2 (a negative regulator) and RARa (a positive regulator) are major determinants of renin expression in whole animals. 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 andpathways.

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 #
5R37HL048058-16
Application #
7544916
Study Section
Special Emphasis Panel (ZRG1-CVS-B (02))
Program Officer
Thrasher, Terry N
Project Start
1993-01-01
Project End
2010-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
16
Fiscal Year
2009
Total Cost
$358,056
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Hu, Chunyan; Lu, Ko-Ting; Mukohda, Masashi et al. (2016) Interference with PPAR? in endothelium accelerates angiotensin II-induced endothelial dysfunction. Physiol Genomics 48:124-34
Lu, Ko-Ting; Keen, Henry L; Weatherford, Eric T et al. (2016) Estrogen Receptor ? Is Required for Maintaining Baseline Renin Expression. Hypertension 67:992-9
Littlejohn, Nicole K; Keen, Henry L; Weidemann, Benjamin J et al. (2016) Suppression of Resting Metabolism by the Angiotensin AT2 Receptor. Cell Rep 16:1548-1560
Mukohda, Masashi; Stump, Madeliene; Ketsawatsomkron, Pimonrat et al. (2016) Endothelial PPAR-? provides vascular protection from IL-1?-induced oxidative stress. Am J Physiol Heart Circ Physiol 310:H39-48
Wu, Jing; Sigmund, Curt D (2016) Hypertension: A Disease That Strikes Around the Clock. Hypertension 67:493-5
Shinohara, Keisuke; Liu, Xuebo; Morgan, Donald A et al. (2016) Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension. Hypertension 68:1385-1392
Ketsawatsomkron, Pimonrat; Keen, Henry L; Davis, Deborah R et al. (2016) Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator-Activated Receptor-? Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate-Salt Hypertension. Hypertension 67:214-22
Jin, Hong; Gebska, Milena A; Blokhin, Ilya O et al. (2015) Endothelial PPAR-? protects against vascular thrombosis by downregulating P-selectin expression. Arterioscler Thromb Vasc Biol 35:838-44
Coble, Jeffrey P; Grobe, Justin L; Johnson, Alan Kim et al. (2015) Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. Am J Physiol Regul Integr Comp Physiol 308:R238-49
Jo, Fusakazu; Jo, Hiromi; Hilzendeger, Aline M et al. (2015) Brain endoplasmic reticulum stress mechanistically distinguishes the saline-intake and hypertensive response to deoxycorticosterone acetate-salt. Hypertension 65:1341-8

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