Journal article
The -20 and -217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells
Hypertension (Dallas, Tex. 1979), Vol.49(3), pp.631-639
03/2007
DOI: 10.1161/01.HYP.0000254350.62876.b1
PMID: 17200439
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, beta-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 beta-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.
Details
- Title: Subtitle
- The -20 and -217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells
- Creators
- Matthew E Dickson - Interdisciplinary Genetics Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City 52242, USAM Bridget ZimmermanKamal RahmouniCurt D Sigmund
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.49(3), pp.631-639
- DOI
- 10.1161/01.HYP.0000254350.62876.b1
- PMID
- 17200439
- NLM abbreviation
- Hypertension
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Publisher
- United States
- Grant note
- HL61446 / NHLBI NIH HHS HL48058 / NHLBI NIH HHS HL55006 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS
- Language
- English
- Date published
- 03/2007
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biostatistics; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9983997476402771
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