ROLE OF ENHANCERS REGULATING RENIN GENE EXPRESSION

Summary

Principal Investigator: CURT DANIEL SIGMUND
Abstract: 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. RELEVANCE (See instructions): 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
Funding Period: 1993-01-01 - 2015-11-30
more information: NIH RePORT

Top Publications

  1. pmc Activity of protein kinase C-α within the subfornical organ is necessary for fluid intake in response to brain angiotensin
    Jeffrey P Coble
    From the Departments of Pharmacology J P C, J L G, C D S, Psychology R F J, A K J, and Anatomy and Cell Biology M D C, Roy J and Lucille A Carver College of Medicine, University of Iowa
    Hypertension 64:141-8. 2014
  2. pmc Peroxisome proliferator-activated receptor-γ protects against vascular aging
    Mary L Modrick
    Department of Internal Medicine, Cardiovascular Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 1081, USA
    Am J Physiol Regul Integr Comp Physiol 302:R1184-90. 2012
  3. pmc Regulation of renin expression by the orphan nuclear receptors Nr2f2 and Nr2f6
    Eric T Weatherford
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Renal Physiol 302:F1025-33. 2012
  4. pmc Divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system
    Curt D Sigmund
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, 52242, USA
    Am J Physiol Regul Integr Comp Physiol 302:R313-20. 2012
  5. pmc Renal proximal tubule angiotensin AT1A receptors regulate blood pressure
    Huiping Li
    Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Am J Physiol Regul Integr Comp Physiol 301:R1067-77. 2011
  6. pmc Inflaming hypothalamic neurons raises blood pressure
    Kamal Rahmouni
    Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
    Cell Metab 14:3-4. 2011
  7. pmc Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation
    Shannon M Harlan
    Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
    Circ Res 108:808-12. 2011
  8. pmc Angiotensinergic signaling in the brain mediates metabolic effects of deoxycorticosterone (DOCA)-salt in C57 mice
    Justin L Grobe
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, 3181 MERF, 375 Newton Rd, Iowa City, IA 52242, USA
    Hypertension 57:600-7. 2011
  9. pmc Neuron- or glial-specific ablation of secreted renin does not affect renal renin, baseline arterial pressure, or metabolism
    Di Xu
    Interdisciplinary Genetics Program, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
    Physiol Genomics 43:286-94. 2011
  10. pmc The brain Renin-angiotensin system controls divergent efferent mechanisms to regulate fluid and energy balance
    Justin L Grobe
    Department of Internal Medicine, University of Iowa, Iowa City, 52242, USA
    Cell Metab 12:431-42. 2010

Detail Information

Publications47

  1. pmc Activity of protein kinase C-α within the subfornical organ is necessary for fluid intake in response to brain angiotensin
    Jeffrey P Coble
    From the Departments of Pharmacology J P C, J L G, C D S, Psychology R F J, A K J, and Anatomy and Cell Biology M D C, Roy J and Lucille A Carver College of Medicine, University of Iowa
    Hypertension 64:141-8. 2014
    ....
  2. pmc Peroxisome proliferator-activated receptor-γ protects against vascular aging
    Mary L Modrick
    Department of Internal Medicine, Cardiovascular Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 1081, USA
    Am J Physiol Regul Integr Comp Physiol 302:R1184-90. 2012
    ..These findings provide the first evidence that interference with PPARγ function accelerates vascular aging, suggesting a novel role for PPARγ in protecting against age-induced oxidative stress and endothelial dysfunction...
  3. pmc Regulation of renin expression by the orphan nuclear receptors Nr2f2 and Nr2f6
    Eric T Weatherford
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Renal Physiol 302:F1025-33. 2012
    ..We conclude that both Nr2f2 and Nr2f6 negatively regulate renin promoter activity, but may do so by divergent mechanisms...
  4. pmc Divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system
    Curt D Sigmund
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, 52242, USA
    Am J Physiol Regul Integr Comp Physiol 302:R313-20. 2012
    ....
  5. pmc Renal proximal tubule angiotensin AT1A receptors regulate blood pressure
    Huiping Li
    Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Am J Physiol Regul Integr Comp Physiol 301:R1067-77. 2011
    ..These data, from two separate mouse models, provide evidence that ANG II signaling via the type 1A receptor in the renal proximal tubule is a regulator of systemic blood pressure under baseline conditions...
  6. pmc Inflaming hypothalamic neurons raises blood pressure
    Kamal Rahmouni
    Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
    Cell Metab 14:3-4. 2011
    ..A recent paper in Nature Medicine (Purkayastha et al., 2011) suggests that obesity and hypertension are caused by inflammation in distinct hypothalamic neuronal populations...
  7. pmc Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation
    Shannon M Harlan
    Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
    Circ Res 108:808-12. 2011
    ..The hypothalamic arcuate nucleus (ARC) is considered a major site for leptin signaling that regulates several physiological processes...
  8. pmc Angiotensinergic signaling in the brain mediates metabolic effects of deoxycorticosterone (DOCA)-salt in C57 mice
    Justin L Grobe
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, 3181 MERF, 375 Newton Rd, Iowa City, IA 52242, USA
    Hypertension 57:600-7. 2011
    ..Together, these data illustrate the necessity of angiotensinergic signaling within the brain, independent of blood pressure alterations, in the metabolic consequences of DOCA-salt treatment...
  9. pmc Neuron- or glial-specific ablation of secreted renin does not affect renal renin, baseline arterial pressure, or metabolism
    Di Xu
    Interdisciplinary Genetics Program, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
    Physiol Genomics 43:286-94. 2011
    ..These data demonstrate that sREN is dispensable within the brain for normal physiological regulation of cardiovascular, hydromineral, and metabolic regulation, and thereby indirectly support the importance of icREN in brain RAS function...
  10. pmc The brain Renin-angiotensin system controls divergent efferent mechanisms to regulate fluid and energy balance
    Justin L Grobe
    Department of Internal Medicine, University of Iowa, Iowa City, 52242, USA
    Cell Metab 12:431-42. 2010
    ..adrenergic blockade or restoration of circulating angiotensin-II, but not adrenalectomy, normalized metabolic rate. Our data point to contrasting mechanisms by which the brain RAS regulates fluid intake and energy expenditure...
  11. pmc Metabolic rate regulation by the renin-angiotensin system: brain vs. body
    Justin L Grobe
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, 3181 MERF, 375 Newton Rd, Iowa City, IA 52242, USA
    Pflugers Arch 465:167-75. 2013
    ..Selectively modulating the peripheral RAS or brain RAS may thus provide a more effective treatment paradigm for obesity and obesity-related disorders...
  12. pmc A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity
    Aline M Hilzendeger
    Center on Functional Genomics of Hypertension, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Heart Circ Physiol 303:H197-206. 2012
    ..Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake...
  13. pmc Coex-Rank: An approach incorporating co-expression information for combined analysis of microarray data
    Jinlu Cai
    Genetics Department, Albert Einstein College of Medicine, New York, New York 10461, USA
    J Integr Bioinform 9:208. 2012
    ..The Coex-rank process not only takes advantage of merging the power of multiple methods regarding normalization but also assists in the discovery of functional clusters of genes...
  14. pmc Differential control of calcium homeostasis and vascular reactivity by Ca2+/calmodulin-dependent kinase II
    Anand M Prasad
    Department of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Hypertension 62:434-41. 2013
    ..However, it increased myosin light chain kinase activity. These data suggest that CaMKII activity maintains intracellular calcium homeostasis but is not required for vasoconstriction of mesenteric arteries. ..
  15. pmc Allele-specific expression of angiotensinogen in human subcutaneous adipose tissue
    Sungmi Park
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, USA
    Hypertension 62:41-7. 2013
    ....
  16. pmc Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent
    Nicole K Littlejohn
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Regul Integr Comp Physiol 304:R818-28. 2013
    ..Together, these data support a major role for vasopressin in the hypertension of mice with brain-specific hyperactivity of the RAS and suggest a primary role of V(2) receptors...
  17. pmc Dominant negative PPARγ promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle
    Christopher J Pelham
    Departments of Molecular Physiology and Biophysics, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Regul Integr Comp Physiol 304:R690-701. 2013
    ..These data demonstrate that inhibition of PPARγ function specifically in the vascular endothelium or smooth muscle may contribute to cardiovascular disease...
  18. pmc Angiotensin type 1a receptors in the subfornical organ are required for deoxycorticosterone acetate-salt hypertension
    Aline M Hilzendeger
    Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA
    Hypertension 61:716-22. 2013
    ....
  19. pmc Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPARγ and RhoA/Rho-kinase
    Christopher J Pelham
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Cell Metab 16:462-72. 2012
    ..We conclude that Cullin-3 regulates vascular function and arterial pressure, thus providing a mechanistic link between mutations in Cullin-3 and hypertension in humans...
  20. pmc PPARγ regulates resistance vessel tone through a mechanism involving RGS5-mediated control of protein kinase C and BKCa channel activity
    Pimonrat Ketsawatsomkron
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Circ Res 111:1446-58. 2012
    ..Previous studies suggest these effects may be mediated through the vasculature, but the underlying mechanisms remain unclear...
  21. pmc Cardiovascular consequences of genetic variation at -6/235 in human angiotensinogen using "humanized" gene-targeted mice
    Justin L Grobe
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Hypertension 56:981-7. 2010
    ..These insights may help explain the discrepancies among observational studies that have examined roles for the -6A/235T and -6G/235M angiotensinogen haplotypes in varied human populations...
  22. pmc Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells
    Michael Desch
    Institute of Physiology, University of Regensburg, D 93040 Regensburg, Germany
    Hypertension 55:660-6. 2010
    ..PPARgamma appears to be a relevant transcription factor for the control of renin gene in JG cells...
  23. pmc The microRNA-processing enzyme dicer maintains juxtaglomerular cells
    Maria Luisa S Sequeira-Lopez
    Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
    J Am Soc Nephrol 21:460-7. 2010
    ..We conclude that microRNAs maintain the renin-producing juxtaglomerular cells and the morphologic integrity and function of the kidney...
  24. pmc An androgen-inducible proximal tubule-specific Cre recombinase transgenic model
    Huiping Li
    Dept of Internal Medicine, 3181B Medical Education and Biomedical Research Facility, Roy J and Lucille A Carver College of Medicine, Univ of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Renal Physiol 294:F1481-6. 2008
    ..This has advantages over other current models where Cre recombinase expression is constitutive, not inducible...
  25. pmc Interference with PPAR gamma function in smooth muscle causes vascular dysfunction and hypertension
    Carmen M Halabi
    Genetics Program, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Cell Metab 7:215-26. 2008
    ..These results identify PPARgamma as pivotal in vascular muscle as a regulator of vascular structure, vascular function, and blood pressure, potentially explaining some of the cardioprotective effects of thiazolidinediones...
  26. pmc Interference with PPARgamma signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling
    Andreas M Beyer
    Genetics Graduate Program, Lucille A Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA
    Hypertension 51:867-71. 2008
    ..These findings indicate that PPARgamma has vascular effects which are particularly profound in the cerebral circulation and provide genetic evidence that PPARgamma plays a critical role in protecting blood vessels...
  27. pmc Chorionic enhancer is dispensable for regulated expression of the human renin gene
    Xiyou Zhou
    Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Regul Integr Comp Physiol 294:R279-87. 2008
    ..These data provide convincing evidence that the CE is silent in vivo, at least in the mouse. The absence of a phenotype caused by deletion of the CE is consistent with the observation that the sequence is not evolutionarily conserved...
  28. pmc Local production of angiotensin II in the subfornical organ causes elevated drinking
    Koji Sakai
    Department of Internal Medicine, Department of Anatomy and Cell Biology, and Center on Functional Genomics of Hypertension, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Clin Invest 117:1088-95. 2007
    ..These data provide strong genetic evidence implicating de novo synthesis of Ang II in the SFO as an integral player in fluid homeostasis...
  29. ncbi The -20 and -217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells
    Matthew E Dickson
    Interdisciplinary Genetics Program, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City 52242, USA
    Hypertension 49:631-9. 2007
    ..Therefore, our data support a hypothesis that polymorphisms in the angiotensinogen promoter may act cell specifically to differentially regulate the level of angiotensinogen transcription in angiotensin-producing tissues...
  30. ncbi Functional characterization of polymorphisms in the kidney enhancer of the human renin gene
    Hana A Itani
    Molecular and Cellular Biology Interdisciplinary Graduate Program, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Endocrinology 148:1424-30. 2007
    ....
  31. ncbi The human renin kidney enhancer is required to maintain base-line renin expression but is dispensable for tissue-specific, cell-specific, and regulated expression
    Xiyou Zhou
    Molecular and Cellular Biology Graduate Program, Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Biol Chem 281:35296-304. 2006
    ..Our results suggest that sequences other than the enhancer may be necessary for tissue-specific, cell-specific, and regulated expression of human RENIN...
  32. ncbi Interleukin-1beta attenuates renin gene expression via a mitogen-activated protein kinase kinase-extracellular signal-regulated kinase and signal transducer and activator of transcription 3-dependent mechanism in As4.1 cells
    Xuebo Liu
    Department of Internal Medicine, 3181B Medical Education and Biomedical Research Facility, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    Endocrinology 147:6011-8. 2006
    ..We conclude that in As4.1 cells, IL-1beta down-regulates renin gene expression via a mechanism involving the Erk-STAT3 pathway...
  33. pmc Dysregulated human renin expression in transgenic mice carrying truncated genomic constructs: evidence supporting the presence of insulators at the renin locus
    Xiyou Zhou
    Molecular and Cellular Graduate Program, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Renal Physiol 295:F642-53. 2008
    ..The study illustrates the value of taking a much wider genomic perspective when studying mechanisms regulating gene expression...
  34. pmc Endothelium-specific interference with peroxisome proliferator activated receptor gamma causes cerebral vascular dysfunction in response to a high-fat diet
    Andreas M Beyer
    Genetics Graduate Program, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Circ Res 103:654-61. 2008
    ..Consistent with its role as a fatty acid sensor, these findings provide genetic evidence that endothelial PPARgamma plays a critical role in protecting blood vessels in response to a high-fat diet...
  35. pmc An intracellular renin-angiotensin system in neurons: fact, hypothesis, or fantasy
    Justin L Grobe
    Department of Internal Medicine, Center on Functional Genomics of Hypertension, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, USA
    Physiology (Bethesda) 23:187-93. 2008
    ..We review evidence for neuronal production of angiotensin peptides and hypothesize that angiotensin may be synthesized intracellularly in neurons...
  36. pmc Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta
    Henry L Keen
    Department of Internal Medicine and Department of Molecular Physiology and Biophysics, 3181B Medical Education and Biomedical Research Facility, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Arterioscler Thromb Vasc Biol 30:518-25. 2010
    ..We hypothesize that these PPARgamma mutants regulate target genes opposite to those of ligand-mediated activation, and we tested this hypothesis on a genomewide scale...
  37. pmc Preservation of intracellular renin expression is insufficient to compensate for genetic loss of secreted renin
    Di Xu
    Interdisciplinary Genetics Program, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Hypertension 54:1240-7. 2009
    ....
  38. pmc Ischemia-induced brain damage is enhanced in human renin and angiotensinogen double-transgenic mice
    Shuzhen Chen
    Departments of Pharmacology and Toxicology, Wright State University, Dayton, Ohio, USA
    Am J Physiol Regul Integr Comp Physiol 297:R1526-31. 2009
    ..01); 3) treatment with losartan (20 micromol/l) abolished OGD-induced exaggeration of cell injury seen in R+A+ mice. The data indicate that activation of ANG II/AT(1) signaling is harmful to brain exposed to ischemia...
  39. pmc Characterization of transgenic mice with neuron-specific expression of soluble epoxide hydrolase
    Robert A Bianco
    Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242, USA
    Brain Res 1291:60-72. 2009
    ..Despite a 3-fold increase in sEH activity in the brain, there was no change in arterial pressure. This data provides new information required for studying the central roles of the cytochrome P450 epoxygenase pathway...
  40. pmc Regulation of renin gene expression by oxidative stress
    Hana Itani
    Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, IA 52242, USA
    Hypertension 53:1070-6. 2009
    ..Our data further suggest that tumor necrosis factor-alpha decreases renin expression through both NFkappaB-dependent and NFkappaB-independent mechanisms, the latter involving the production of reactive oxygen species...
  41. pmc Upstream stimulatory factor is required for human angiotensinogen expression and differential regulation by the A-20C polymorphism
    Matthew E Dickson
    Genetics and Medical Scientist Training Programs, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
    Circ Res 103:940-7. 2008
    ..We conclude that USF1 functionally and differentially regulates AGT expression via the -20 polymorphism and that the differential expression exhibited by -20 can be accounted for by differential association with USF1...
  42. ncbi Evidence supporting a functional role for intracellular renin in the brain
    Julie L Lavoie
    Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
    Hypertension 47:461-6. 2006
    ..These data support the concept of an intracellular form of renin in the brain, which may provoke functional changes in fluid homeostasis and BP regulation...