Published online before print January 25, 2007, doi: 10.1161/01.RES.0000258855.60637.58
© 2007 American Heart Association, Inc.
Molecular Medicine |
Epigenetic Modification of the Renin-Angiotensin System in the Fetal Programming of Hypertension
From the Centre for Endocrinology (I.B., S.W., P.J.K., A.J.L.C.), Barts & the London, Queen Mary University of London, UK; Department of Chemical and Biological Sciences (S.P.B.), University of Huddersfield, UK.
Correspondence to Professor A.J.L. Clark, Centre for Endocrinology, John Vane Science Centre, William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, UK. E-mail a.j.clark{at}qmul.ac.uk
Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Lifelong environmental factors (eg, salt intake, obesity, alcohol) and genetic factors clearly contribute to the development of hypertension, but it has also been established that stress in utero may program the later development of the disease. This phenomenon, known as fetal programming can be modeled in a range of experimental animal models. In maternal low protein diet rat models of programming, administration of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists in early life can prevent development of hypertension, thus implicating the renin-angiotensin system in this process. Here we show that in this model, expression of the AT1b angiotensin receptor gene in the adrenal gland is upregulated by the first week of life resulting in increased receptor protein expression consistent with the increased adrenal angiotensin responsiveness observed by others. Furthermore, we show that the proximal promoter of the AT1b gene in the adrenal is significantly undermethylated, and that in vitro, AT1b gene expression is highly dependent on promoter methylation. These data suggest a link between fetal insults to epigenetic modification of genes and the resultant alteration of gene expression in adult life leading ultimately to the development of hypertension. It seems highly probable that similar influences may be involved in the development of human hypertension.
Key Words: hypertension • angiotensin receptors • fetal programming • DNA methylation
Related Article:
Circ. Res. 2007 100: 452-455.
This article has been cited by other articles:
 |
|
 |
|
  E. W. Tobi, L.H. Lumey, R. P. Talens, D. Kremer, H. Putter, A. D. Stein, P. E. Slagboom, and B. T. Heijmans DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific Hum. Mol. Genet., November 1, 2009; 18(21): 4046 - 4053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Plagemann, T. Harder, M. Brunn, A. Harder, K. Roepke, M. Wittrock-Staar, T. Ziska, K. Schellong, E. Rodekamp, K. Melchior, et al. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome J. Physiol., October 15, 2009; 587(20): 4963 - 4976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Goyal, A. Galffy, S. A. Field, C. P. Gheorghe, A. Mittal, and L. D. Longo Maternal Protein Deprivation: Changes in Systemic Renin-Angiotensin System of the Mouse Fetus Reproductive Sciences, September 1, 2009; 16(9): 894 - 904. [Abstract] [PDF]
|
|
|
|
 |
|
 I. G Bogdarina, P. J King, and A. J L Clark Characterization of the angiotensin (AT1b) receptor promoter and its regulation by glucocorticoids J. Mol. Endocrinol., August 1, 2009; 43(2): 73 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Bell, N. M.K. Lariviere, P. H. Watson, and A. J. Watson Mitogen-activated protein kinase (MAPK) pathways mediate embryonic responses to culture medium osmolarity by regulating Aquaporin 3 and 9 expression and localization, as well as embryonic apoptosis Hum. Reprod., June 1, 2009; 24(6): 1373 - 1386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Alexander Developmental programming of sex-dependent alterations in lipid metabolism: a role for long-term, sex-specific alterations in LDL-receptor expression. Focus on "Developmental programming of lipid metabolism and aortic vascular function in C57BL/6 mice: a novel study suggesting an involvement of LDL-receptor" Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2009; 296(4): R1027 - R1028. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhang, K. D. Meyer, and L. Zhang Fetal Exposure to Cocaine Causes Programming of Prkce Gene Repression in the Left Ventricle of Adult Rat Offspring Biol Reprod, March 1, 2009; 80(3): 440 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Heijmans, E. W. Tobi, A. D. Stein, H. Putter, G. J. Blauw, E. S. Susser, P. E. Slagboom, and L. H. Lumey Persistent epigenetic differences associated with prenatal exposure to famine in humans PNAS, November 4, 2008; 105(44): 17046 - 17049. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. D. Gluckman, M. A. Hanson, C. Cooper, and K. L. Thornburg Effect of In Utero and Early-Life Conditions on Adult Health and Disease N. Engl. J. Med., July 3, 2008; 359(1): 61 - 73. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Stenvinkel and T. J. Ekstrom Epigenetics--a helpful tool to better understand processes in clinical nephrology? Nephrol. Dial. Transplant., May 1, 2008; 23(5): 1493 - 1496. [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Aragon, P. G. Kopf, M. J. Campen, J. K. Huwe, and M. K. Walker In Utero and Lactational 2,3,7,8-Tetrachlorodibenzo-p-dioxin Exposure: Effects on Fetal and Adult Cardiac Gene Expression and Adult Cardiac and Renal Morphology Toxicol. Sci., February 1, 2008; 101(2): 321 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Nuyt and M. Szyf Developmental Programming Through Epigenetic Changes Circ. Res., March 2, 2007; 100(4): 452 - 455. [Full Text] [PDF]
|
|