Published Online
on January 2, 2007

A more recent version of this article appeared on March 1, 2007

This Article Full Text (PDF) Data Supplement All Versions of this Article: 49/3/631    most recent 01.HYP.0000254350.62876.b1v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dickson, M. E. Articles by Sigmund, C. D. Search for Related Content PubMed PubMed Citation Articles by Dickson, M. E. Articles by Sigmund, C. D. Related Collections Other hypertension Gene expression Gene regulation Genomics Genetics of cardiovascular disease

Submitted on October 3, 2006
Revised on October 30, 2006

The -20 and -217 Promoter Variants Dominate Differential Angiotensinogen Haplotype Regulation in Angiotensinogen-Expressing Cells

Matthew E. Dickson; M. Bridget Zimmerman; Kamal Rahmouni; and Curt D. Sigmund^*

From the Interdisciplinary Genetics Program (M.E.D., C.D.S.), Medical Scientist Training Program (M.E.D.), Department of Biostatistics (M.B.Z.), Department of Internal Medicine (K.R., C.D.S.), and Molecular Physiology and Biophysics (C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.

^* To whom correspondence should be addressed. E-mail: curt-sigmund{at}uiowa.edu.

Abstract--A number of naturally occurring polymorphisms exist in the human angiotensinogen locus, some of which have been associated with essential hypertension, preeclampsia, and other medical disorders. However, to date there has been no comprehensive determination of the significance of specific haplotypes in relation to the regulation of angiotensinogen expression. We cloned the promoters extending from -1219 to +125 bp from 11 ethnically diverse individuals to acquire a representative cross-section of known haplotype diversity. Eight nonredundant haplotypes were identified, fused to luciferase, and studied for their effect on transcriptional regulation in human astrocyte, proximal tubule, and hepatocyte cell lines endogenously expressing angiotensinogen and in a mouse adipocyte cell line. The studies were carried out under baseline conditions, in the presence of the angiotensinogen enhancer, and in response to hormonal stimulation by dexamethasone, -estradiol, or testosterone. A statistical model was then constructed to assess the significance of individual polymorphisms. The polymorphisms with the greatest effect on transcription in these cell lines were located at -20 and -217. There were modest haplotype-specific effects of the angiotensinogen enhancer and no haplotype-specific effects of -estradiol, dexamethasone, or testosterone treatment. We conclude the following: (1) the -20 and -217 polymorphisms have the largest influence on angiotensinogen transcription, (2) other polymorphisms have a much smaller impact on angiotensinogen transcription, and (3) the transcriptional influence of the promoter polymorphisms may act cell specifically. 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.

Key words: transcription • genetics • renin-angiotensin system • hypertension • transfection

This article has been cited by other articles:

				S. Jain, G. Vinukonda, S. N. Fiering, and A. Kumar A haplotype of human angiotensinogen gene containing -217A increases blood pressure in transgenic mice compared with -217G Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R1849 - R1857. [Abstract] [Full Text] [PDF]

				C. D. Sigmund A growing chain of evidence linking genetic variation in angiotensinogen with essential hypertension: focus on "A haplotype of human angiotensinogen gene containing -217A increases blood pressure in transgenic mice compared with -217G," by Jain et al. Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R1846 - R1848. [Full Text] [PDF]

				M. E. Dickson, X. Tian, X. Liu, D. R. Davis, and C. D. Sigmund Upstream Stimulatory Factor Is Required for Human Angiotensinogen Expression and Differential Regulation by the A-20C Polymorphism Circ. Res., October 24, 2008; 103(9): 940 - 947. [Abstract] [Full Text] [PDF]

				R. Satou, R. A. Gonzalez-Villalobos, K. Miyata, N. Ohashi, A. Katsurada, L. G. Navar, and H. Kobori Costimulation with angiotensin II and interleukin 6 augments angiotensinogen expression in cultured human renal proximal tubular cells Am J Physiol Renal Physiol, July 1, 2008; 295(1): F283 - F289. [Abstract] [Full Text] [PDF]

				P.-a. B. Shih and D. T. O'Connor Hereditary Determinants of Human Hypertension: Strategies in the Setting of Genetic Complexity Hypertension, June 1, 2008; 51(6): 1456 - 1464. [Full Text] [PDF]

				T. V. Pereira, A. C.F. Nunes, M. Rudnicki, Y. Yamada, A. C. Pereira, and J. E. Krieger Meta-Analysis of the Association of 4 Angiotensinogen Polymorphisms With Essential Hypertension: A Role Beyond M235T? Hypertension, March 1, 2008; 51(3): 778 - 783. [Abstract] [Full Text] [PDF]