Published online before print August 2, 2001, doi: 10.1161/hh1601.094988
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2001 American Heart Association, Inc.
Integrative Physiology |
Elevated Blood Pressure in Transgenic Mice With Brain-Specific Expression of Human Angiotensinogen Driven by the Glial Fibrillary Acidic Protein Promoter
From the Departments of Internal Medicine and Physiology & Biophysics (S.M., C.D.S.), Psychology (T.G.B., A.K.J.), and Anatomy and Cell Biology (M.D.C., R.L.D.), University of Iowa, Iowa City, Iowa.
Correspondence to Curt D. Sigmund, PhD, Departments of Internal Medicine and Physiology and Biophysics, 2191 Medical Laboratory, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail curt-sigmund{at}uiowa.edu
In addition to the circulatory renin (REN)–angiotensin system (RAS), a tissue RAS having an important role in cardiovascular function also exists in the central nervous system. In the brain, angiotensinogen (AGT) is expressed in astrocytes and in some neurons important to cardiovascular control, but its functional role remains undefined. We generated a transgenic mouse encoding the human AGT (hAGT) gene under the control of the human glial fibrillary acidic protein (GFAP) promoter to experimentally dissect the role of brain versus systemically derived AGT. This promoter targets expression of transgene products to astrocytes, the most abundant cell type expressing AGT in brain. All transgenic lines exhibited hAGT mRNA expression in brain, with variable expression in other tissues. In one line examined in detail, transgene expression was high in brain and low in tissues outside the central nervous system, and the level of plasma hAGT was not elevated over baseline. In the brain, hAGT protein was mainly localized in astrocytes, but was present in neurons in the subfornical organ. Intracerebroventricular (ICV) injection of human REN (hREN) in conscious unrestrained mice elicited a pressor response, which was abolished by ICV preinjection of losartan. Double-transgenic mice expressing the hREN gene and the GFAP-hAGT transgene exhibited a 15–mm Hg increase in blood pressure and an increased preference for salt. Blood pressure in the hREN/GFAP-hAGT mice was lowered after ICV, but not intravenous losartan. These studies suggest that AGT synthesis in the brain has an important role in the regulation of blood pressure and electrolyte balance.
Key Words: blood pressure • renin-angiotensin system • brain • astrocyte • transgenic mouse
This article has been cited by other articles:
 |
|
 |
|
  X. Hou, S. F. Theriault, I. Dostanic-Larson, A. E. Moseley, J. B Lingrel, H. Wu, S. Dean, and J. W. Van Huysse Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous {alpha}2 Na+-K+-ATPase knockout mice Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1427 - R1438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Grobe, D. Xu, and C. D. Sigmund An Intracellular Renin-Angiotensin System in Neurons: Fact, Hypothesis, or Fantasy Physiology, August 1, 2008; 23(4): 187 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Feng, X. Yue, H. Xia, S. M. Bindom, P. J. Hickman, C. M. Filipeanu, G. Wu, and E. Lazartigues Angiotensin-Converting Enzyme 2 Overexpression in the Subfornical Organ Prevents the Angiotensin II-Mediated Pressor and Drinking Responses and Is Associated With Angiotensin II Type 1 Receptor Downregulation Circ. Res., March 28, 2008; 102(6): 729 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Orlov and A. A. Mongin Salt-sensing mechanisms in blood pressure regulation and hypertension Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2039 - H2053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Kistler, P. Sanders, M. Dodic, S. J. Spence, C. S. Samuel, C. Zhao, J. A. Charles, G. A. Edwards, and J. M. Kalman Atrial electrical and structural abnormalities in an ovine model of chronic blood pressure elevation after prenatal corticosteroid exposure: implications for development of atrial fibrillation Eur. Heart J., December 2, 2006; 27(24): 3045 - 3056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sinnayah, E. Lazartigues, K. Sakai, R. V. Sharma, C. D. Sigmund, and R. L. Davisson Genetic Ablation of Angiotensinogen in the Subfornical Organ of the Brain Prevents the Central Angiotensinergic Pressor Response Circ. Res., November 10, 2006; 99(10): 1125 - 1131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Lavoie, X. Liu, R. A. Bianco, T. G. Beltz, A. K. Johnson, and C. D. Sigmund Evidence Supporting a Functional Role for Intracellular Renin in the Brain Hypertension, March 1, 2006; 47(3): 461 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sherrod, D. R. Davis, X. Zhou, M. D. Cassell, and C. D. Sigmund Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1763 - R1769. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sherrod, X. Liu, X. Zhang, and C. D. Sigmund Nuclear localization of angiotensinogen in astrocytes Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2005; 288(2): R539 - R546. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sakai, M. W. Chapleau, S. Morimoto, M. D. Cassell, and C. D. Sigmund Differential modulation of baroreflex control of heart rate by neuron- vs. glia-derived angiotensin II Physiol Genomics, December 15, 2004; 20(1): 66 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-C. Fournie-Zaluski, C. Fassot, B. Valentin, D. Djordjijevic, A. Reaux-Le Goazigo, P. Corvol, B. P. Roques, and C. Llorens-Cortes Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension PNAS, May 18, 2004; 101(20): 7775 - 7780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Lavoie, K. D. Lake-Bruse, and C. D. Sigmund Increased blood pressure in transgenic mice expressing both human renin and angiotensinogen in the renal proximal tubule Am J Physiol Renal Physiol, May 1, 2004; 286(5): F965 - F971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Lavoie, M. D. Cassell, K. W. Gross, and C. D. Sigmund Adjacent Expression of Renin and Angiotensinogen in the Rostral Ventrolateral Medulla Using a Dual-Reporter Transgenic Model Hypertension, May 1, 2004; 43(5): 1116 - 1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Lavoie, M. D. Cassell, K. W. Gross, and C. D. Sigmund Localization of renin expressing cells in the brain, by use of a REN-eGFP transgenic model Physiol Genomics, January 15, 2004; 16(2): 240 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Davisson Physiological genomic analysis of the brain renin-angiotensin system Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2003; 285(3): R498 - R511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Johnson, T. G. Beltz, R. L. Thunhorst, and A. K. Johnson Investigations on the physiological controls of water and saline intake in C57BL/6 mice Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R394 - R403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Lavoie and C. D. Sigmund Minireview: Overview of the Renin-Angiotensin System--An Endocrine and Paracrine System Endocrinology, June 1, 2003; 144(6): 2179 - 2183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dodic, T. Abouantoun, A. O'Connor, E. M. Wintour, and K. M. Moritz Programming Effects of Short Prenatal Exposure to Dexamethasone in Sheep Hypertension, November 1, 2002; 40(5): 729 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Morimoto, M. D. Cassell, and C. D. Sigmund Glia- and Neuron-specific Expression of the Renin-Angiotensin System in Brain Alters Blood Pressure, Water Intake, and Salt Preference J. Biol. Chem., August 30, 2002; 277(36): 33235 - 33241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Morimoto, M. D. Cassell, and C. D. Sigmund Neuron-specific expression of human angiotensinogen in brain causes increased salt appetite Physiol Genomics, May 10, 2002; 9(2): 113 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. B. Glueck and V. J. Dzau Physiological Genomics: Implications In Hypertension Research Hypertension, February 1, 2002; 39(2): 310 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Stec, H. L. Keen, and C. D. Sigmund Lower Blood Pressure in Floxed Angiotensinogen Mice After Adenoviral Delivery of Cre-Recombinase Hypertension, February 1, 2002; 39(2): 629 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bader and D. Ganten It's Renin in the Brain: Transgenic Animals Elucidate the Brain Renin-Angiotensin System Circ. Res., January 11, 2002; 90(1): 8 - 10. [Full Text] [PDF]
|
|
|
|
|
|
S. Morimoto, M. D. Cassell, and C. D. Sigmund The Brain Renin-Angiotensin System in Transgenic Mice Carrying a Highly Regulated Human Renin Transgene Circ. Res., January 11, 2002; 90(1): 80 - 86. [Abstract] [Full Text] [PDF]
|
|