Skip to main content
SpringerLink
Log in

Local Production of Angiotensinogen

Insights From Genetic Manipulation of Mice

  • Chapter
Cardiovascular Genomics

Part of the book series: Contemporary Cardiology ((CONCARD))

  • 531 Accesses

Abstract

Genetic approaches such as gene targeting have been extensively used to gain a better understanding of the role of hormones and pathways involved in cardiovascular physiology. Given its pivotal role in cardiovascular homeostasis the renin-angiotensin system has been one of the most frequently targeted systems. Angiotensinogen (AGT), the only known precursor of the renin-angiotensin system, has received particular attention because genetic and molecular studies have shown that genetic variation at this locus impacts individual differences in blood pressure and the likelihood of developing essential hypertension. Knockout and overexpression of the AGT gene lead to adverse cardiovascular phenotypes. In this chapter we will review these data and detail a strategy using well-characterized cell-specific promoters to specifically target the AGT gene to defined cells and tissues. The development and characterization of these models has helped uncover the role and significance of local production of AGT in several tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Reid IA, Morris BJ, Ganong WF. The renin-angiotensin system. Annu Rev Physiol 1978;40:377–410.

    Article  PubMed  CAS  Google Scholar 

  2. Campbell DJ. Circulating and tissue angiotensin systems. J Clin Invest 1987;79:1–6.

    Article  PubMed  CAS  Google Scholar 

  3. Schmidt-Ott KM, Kagiyama S, Phillips MI. The multiple actions of angiotensin II in atherosclerosis. Regul Pept 2000;93:65–77.

    Article  PubMed  CAS  Google Scholar 

  4. Gomez RA, Norwood VF. Developmental consequences of the renin-angiotensin system. Am J Kidney Dis 1995;26:409–431.

    PubMed  CAS  Google Scholar 

  5. Bader M, Peters J, Baltatu O, Muller DN, Luft FC, Ganten D. Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research. J Mol Med 2001;79:76–102.

    Article  PubMed  CAS  Google Scholar 

  6. Lavoie JL, Sigmund CD. Minireview: overview of the renin-angiotensin system—an endocrine and paracrine system. Endocrinology 2003;144:2179–2183.

    Article  PubMed  CAS  Google Scholar 

  7. Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al. Molecular Basis of Human Hypertension: Role of Angiotensinogen. Cell 1992;71:169–180.

    Article  PubMed  CAS  Google Scholar 

  8. Watt GC, Harrap SB, Foy CJ, et al. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure. J Hypertens 1992;10:473–482.

    Article  PubMed  CAS  Google Scholar 

  9. Ohkubo H, Kawakami H, Kakehi Y, et al. Generation of transgenic mice with elevated blood pressure by introduction of the rat renin and angiotensinogen genes. Proc Natl Acad Sci USA 1990;87:5153–5157.

    Article  PubMed  CAS  Google Scholar 

  10. Tanimoto K, Sugiyama F, Goto Y, et al. Angiotensinogen-deficient mice with hypotension. J Biol Chem 1994;269:31,334–31,337.

    PubMed  CAS  Google Scholar 

  11. Kim HS, Krege JH, Kluckman KD, et al. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA 1995;92:2735–2739.

    Article  PubMed  CAS  Google Scholar 

  12. Hatae T, Takimoto E, Murakami K, Fukamizu A. Comparative studies on species-specific reactivity between renin and angiotensinogen. Mol Cell Biochem 1994;131:43–47.

    Article  PubMed  CAS  Google Scholar 

  13. Ganten D, Wagner J, Zeh K, et al. Species-specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes. Proc Natl Acad Sci USA 1992;89:7806–7810.

    Article  PubMed  CAS  Google Scholar 

  14. Yang G, Merrill DC, Thompson MW, Robillard JE, Sigmund CD. Functional expression of the human angiotensinogen gene in transgenic mice. J Biol Chem 1994;269:32497–32502.

    PubMed  CAS  Google Scholar 

  15. Brasier AR, Li JY. Mechanisms for inducible control of angiotensinogen gene transcription. Hypertension 1996;27:465–475.

    PubMed  CAS  Google Scholar 

  16. Deschepper CF. Angiotensinogen: Hormonal regulation and relative importance in the generation of angiotensin II. Kidney Int 1994;46:1561–1563.

    Article  PubMed  CAS  Google Scholar 

  17. Nagata M, Tanimoto K, Fukamizu A, et al. Nephrogenesis and renovascular development in angiotensinogen-deficient mice. Lab Invest 1996;75:745–753.

    PubMed  CAS  Google Scholar 

  18. Ingelfinger JR, Zuo WM, Fon EA, Ellison KE, Dzau VJ. In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system. J Clin Invest 1990;85:417–423.

    PubMed  CAS  Google Scholar 

  19. Merrill DC, Thompson MW, Carney C, Schlager G, Robillard JE, Sigmund CD. Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. J Clin Invest 1996;97:1047–1055.

    Article  PubMed  CAS  Google Scholar 

  20. Davisson RL, Kim HS, Krege JH, Lager DJ, Smithies O, Sigmund CD. Complementation of reduced survival, hypotension and renal abnormalities in angiotensinogen deficient mice by the human renin and human angiotensinogen genes. J Clin Invest 1997;99:1258–1264.

    PubMed  CAS  Google Scholar 

  21. Kilby NJ, Snaith MR, Murray JAH. Site-specific recombinases: tools for genome engineering. Trends Genet 1994;9:413–421.

    Article  Google Scholar 

  22. Stec DE, Davisson RL, Haskell RE, Davidson BL, Sigmund CD. Efficient liver-specific deletion of a floxed human angiotensinogen transgene by adenoviral delivery of cre-recombinase in vivo. J Biol Chem 1999;274:21,285–21,290.

    Article  PubMed  CAS  Google Scholar 

  23. Bosch A, McCray PBJ, Chang SM, et al. Proliferation induced by keratinocyte growth factor enhances in vivo retroviral-mediated gene transfer to mouse hepatocytes. J Clin Invest 1996;98:2683–2687.

    PubMed  CAS  Google Scholar 

  24. Stec DE, Keen HL, Sigmund CD. Lower blood pressure in floxed angiotensinogen mice after adenoviral delivery of cre-recombinase. Hypertension 2002;39:629–633.

    Article  PubMed  CAS  Google Scholar 

  25. Matsusue K, Haluzik M, Lambert G, et al. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 2003;111:737–747.

    Article  PubMed  CAS  Google Scholar 

  26. Wang CT, Navar LG, Mitchell KD. Proximal tubular fluid angiotensin II levels in angiotensin II-induced hypertensive rats. J Hypertens 2003;21:353–360.

    Article  PubMed  Google Scholar 

  27. Kobori H, Harrison-Bernard LM, Navar LG. Urinary excretion of angiotensinogen reflects intrarenal angiotensinogen production. Kidney Int 2002;61:579–585.

    Article  PubMed  CAS  Google Scholar 

  28. Loghman-Adham M, Rohrwasser A, Helin C, et al. A conditionally immortalized cell line from murine proximal tubule. Kidney Int 1997;52:229–239.

    Article  PubMed  CAS  Google Scholar 

  29. Ding Y, Sigmund CD. Androgen-Dependent Regulation of Human Angiotensinogen Expression in KAP-hAGT Transgenic Mice. Am J Physiol: Renal Physiol 2001;280:F54–F60.

    CAS  Google Scholar 

  30. Davisson RL, Ding Y, Stec DE, Catterall JF, Sigmund CD. Novel mechanism of hypertension revealed by cell-specific targeting of human angiotensinogen in transgenic mice. Physiol Genomics 1999;1:3–9.

    PubMed  CAS  Google Scholar 

  31. Ding Y, Davisson RL, Hardy DO, Zhu L-J, Merrill DC, Catterall JF, Sigmund CD. The kidney androgen-regulated protein (KAP) promoter confers renal proximal tubule cell-specific and highly androgen-responsive expression on the human angiotensinogen gene in transgenic mice. J Biol Chem 1997;272:28,142–28,148.

    Article  PubMed  CAS  Google Scholar 

  32. Meseguer A, Catterall JF. Androgen regulated expression of kidney androgen-regulated protein mRNA is localized in the epithelial cells of the murine renal proximal convoluted tubules. Mol Endocrinol 1987;1:535–541.

    PubMed  CAS  Google Scholar 

  33. Paul M, Bader M, Steckelings UM, Voigtlander T, Ganten D. The renin-angiotensin system in the brain. Localization and functional significance. [Review]. Arzneimittel-Forschung 1993;43:207–213.

    PubMed  CAS  Google Scholar 

  34. Sernia C. Location and secretion of brain angiotensinogen. [Review]. Regulatory Peptides 1995;57:1–18.

    Article  PubMed  CAS  Google Scholar 

  35. Morimoto S, Cassell MD, Sigmund CD. The Brain Renin-angiotensin System in Transgenic Mice Carrying a Highly Regulated Human Renin Transgene. Circ Res 2002;90:80–86.

    Article  PubMed  CAS  Google Scholar 

  36. Lavoie JL, Cassell MD, Gross KW, Sigmund CD. Localization of Renin Expressing Cells in the Brain Using a REN-eGFP Transgenic Model. Physiol Genomics 2004;16:240–246.

    PubMed  CAS  Google Scholar 

  37. Stornetta RL, Hawelu Johnson CL, Guyenet PG, Lynch KR. Astrocytes synthesize angiotensinogen in brain. Science 1988;242:1444–1446.

    Article  PubMed  CAS  Google Scholar 

  38. Morimoto S, Cassell MD, Beltz TG, Johnson AK, Davisson RL, Sigmund CD. Elevated blood pressure in transgenic mice with brain-specific expression of human angiotensinogen driven by the glial fibrillary acidic protein promoter. Circ Res 2001;89:365–372.

    Article  PubMed  CAS  Google Scholar 

  39. Morimoto S, Cassell MD, Sigmund CD. Glial-and neuronal-specific expression of the renin-angiotensin system in brain alters blood pressure, water intake, and salt preference. J Biol Chem 2002;277:33,235–33,241.

    Article  PubMed  CAS  Google Scholar 

  40. Schinke M, Baltatu O, Bohm M, et al. Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen. Proc Natl Acad Sci USA 1999;96:3975–3980.

    Article  PubMed  CAS  Google Scholar 

  41. Lochard N, Silversides DW, Van Kats JP, Mercure C, Reudelhuber TL. Brain-specific restoration of angiotensin II corrects renal defects seen in angiotensinogen-deficient mice. J Biol Chem 2002;278:2184–2189.

    Article  PubMed  CAS  Google Scholar 

  42. Morimoto S, Cassell MD, Sigmund CD. Neuron-specific expression of human angiotensinogen in brain causes increased salt appetite. Physiol Genomics 2002;9:113–120.

    PubMed  CAS  Google Scholar 

  43. Lazartigues E, Dunlay SM, Loihl AK, et al. Brain-selective overexpression of angiotensin (AT1) receptors causes enhanced cardiovascular sensitivity in transgenic mice. Circ Res 2002;90:617–624.

    Article  PubMed  CAS  Google Scholar 

  44. Bader M. Role of the local renin-angiotensin system in cardiac damage: a minireview focussing on transgenic animal models. J Mol Cell Cardiol 2002;34:1455–1462.

    Article  PubMed  CAS  Google Scholar 

  45. Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev 2003;24:261–271.

    Article  PubMed  CAS  Google Scholar 

  46. Tamura K, Umemura S, Nyui N, et al. Tissue-specific regulation of angiotensinogen gene expression in spontaneously hypertensive rats. Hypertension 1996;27:1216–1223.

    PubMed  CAS  Google Scholar 

  47. Serneri GG, Boddi M, Cecioni I, et al. Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function. Circ Res 2001;88:961–968.

    Article  PubMed  CAS  Google Scholar 

  48. Mazzolai L, Nussberger J, Aubert JF, et al. Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system. Hypertension 1998;31:1324–1330.

    PubMed  CAS  Google Scholar 

  49. Methot D, LaPointe MC, Touyz RM, et al. Tissue targeting of angiotensin peptides. J Biol Chem 1997;272:12,994–12,999.

    Article  PubMed  CAS  Google Scholar 

  50. Kang N, Walther T, Tian XL, et al. Reduced hypertension-induced end-organ damage in mice lacking cardiac and renal angiotensinogen synthesis. J Mol Med 2002;80:359–366.

    Article  PubMed  CAS  Google Scholar 

  51. Bradley RL, Cleveland KA, Cheatham B. The adipocyte as a secretory organ: mechanisms of vesicle transport and secretory pathways. Recent Prog Horm Res 2001;56:329–358.

    Article  PubMed  CAS  Google Scholar 

  52. Engeli S, Negrel R, Sharma AM. Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 2000;35:1270–1277.

    PubMed  CAS  Google Scholar 

  53. Goossens GH, Blaak EE, van Baak MA. Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Obes Rev 2003;4:43–55.

    Article  PubMed  CAS  Google Scholar 

  54. Massiera F, Bloch-Faure M, Ceiler D, et al. Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. FASEB J 2001;15:2727–2729.

    PubMed  CAS  Google Scholar 

  55. Rahmouni K, Mark AL, Haynes WG, Sigmund CD. Adipose depot-specific modulation of angiotensinogen gene expression in diet-induced obesity. Am J Physiol: Endocrinol Metabol 2004;286:E891–E895.

    Article  CAS  Google Scholar 

  56. Stec DE, Sigmund CD. Modifiable gene expression in kidney: kidney-specific deletion of a target gene via the cre-loxP system. Exp Nephrol 1998;6:568–575.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiovascular Center, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA

    Kamal Rahmouni & Curt D. Sigmund PhD

Authors
  1. Kamal Rahmouni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Curt D. Sigmund PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL

    Mohan K. Rai ADA PhD

  2. Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK

    Julian F. R. Paton PhD  & Sergey Kasparov MD, PhD  & 

  3. Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, FL

    Michael J. Katovich PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Humana Press Inc.

About this chapter

Cite this chapter

Rahmouni, K., Sigmund, C.D. (2005). Local Production of Angiotensinogen. In: Rai, M.K., Paton, J.F.R., Kasparov, S., Katovich, M.J. (eds) Cardiovascular Genomics. Contemporary Cardiology. Humana Press. https://doi.org/10.1385/1-59259-883-8:059

Download citation

  • DOI: https://doi.org/10.1385/1-59259-883-8:059

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-400-5

  • Online ISBN: 978-1-59259-883-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation