A polymorphism in intron I of the human angiotensinogen gene (hAGT) affects binding by HNF3 and hAGT expression and increases blood pressure in mice
© 2019 Mopidevi et al..
Angiotensinogen (AGT) is the precursor of one of the most potent vasoconstrictors, peptide angiotensin II. Genome-wide association studies have shown that two A/G polymorphisms (rs2493134 and rs2004776), located at +507 and +1164 in intron I of the human AGT (hAGT) gene, are associated with hypertension. Polymorphisms of the AGT gene result in two main haplotypes. Hap-I contains the variants -217A, -6A, +507G, and +1164A and is pro-hypertensive, whereas Hap-II contains the variants -217G, -6G, +507A, and +1164G and does not affect blood pressure. The nucleotide sequence of intron I of the hAGT gene containing the +1164A variant has a stronger homology with the hepatocyte nuclear factor 3 (HNF3)-binding site than +1164G. Here we found that an oligonucleotide containing +1164A binds HNF3β more strongly than +1164G and that Hap-I-containing reporter gene constructs have increased basal and HNF3- and glucocorticoid-induced promoter activity in transiently transfected liver and kidney cells. Using a knock-in approach at the hypoxanthine-guanine phosphoribosyltransferase locus, we generated a transgenic mouse model containing the human renin (hREN) gene and either Hap-I or Hap-II. We show that transgenic animals containing Hap-I have increased blood pressure compared with those containing Hap-II. Moreover, the transcription factors glucocorticoid receptor, CCAAT enhancer-binding protein β, and HNF3β bound more strongly to chromatin obtained from the liver of transgenic animals containing Hap-I than to liver chromatin from Hap-II-containing animals. These findings suggest that, unlike Hap-II variants, Hap-I variants of the hAGT gene have increased transcription rates, resulting in elevated blood pressure.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2019 |
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Erschienen: |
2019 |
Enthalten in: |
Zur Gesamtaufnahme - volume:294 |
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Enthalten in: |
The Journal of biological chemistry - 294(2019), 31 vom: 02. Aug., Seite 11829-11839 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Mopidevi, Brahmaraju [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 16.03.2020 Date Revised 10.04.2022 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1074/jbc.RA119.007715 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM298178745 |
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100 | 1 | |a Mopidevi, Brahmaraju |e verfasserin |4 aut | |
245 | 1 | 2 | |a A polymorphism in intron I of the human angiotensinogen gene (hAGT) affects binding by HNF3 and hAGT expression and increases blood pressure in mice |
264 | 1 | |c 2019 | |
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520 | |a © 2019 Mopidevi et al. | ||
520 | |a Angiotensinogen (AGT) is the precursor of one of the most potent vasoconstrictors, peptide angiotensin II. Genome-wide association studies have shown that two A/G polymorphisms (rs2493134 and rs2004776), located at +507 and +1164 in intron I of the human AGT (hAGT) gene, are associated with hypertension. Polymorphisms of the AGT gene result in two main haplotypes. Hap-I contains the variants -217A, -6A, +507G, and +1164A and is pro-hypertensive, whereas Hap-II contains the variants -217G, -6G, +507A, and +1164G and does not affect blood pressure. The nucleotide sequence of intron I of the hAGT gene containing the +1164A variant has a stronger homology with the hepatocyte nuclear factor 3 (HNF3)-binding site than +1164G. Here we found that an oligonucleotide containing +1164A binds HNF3β more strongly than +1164G and that Hap-I-containing reporter gene constructs have increased basal and HNF3- and glucocorticoid-induced promoter activity in transiently transfected liver and kidney cells. Using a knock-in approach at the hypoxanthine-guanine phosphoribosyltransferase locus, we generated a transgenic mouse model containing the human renin (hREN) gene and either Hap-I or Hap-II. We show that transgenic animals containing Hap-I have increased blood pressure compared with those containing Hap-II. Moreover, the transcription factors glucocorticoid receptor, CCAAT enhancer-binding protein β, and HNF3β bound more strongly to chromatin obtained from the liver of transgenic animals containing Hap-I than to liver chromatin from Hap-II-containing animals. These findings suggest that, unlike Hap-II variants, Hap-I variants of the hAGT gene have increased transcription rates, resulting in elevated blood pressure | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a angiotensin | |
650 | 4 | |a cardiovascular disease | |
650 | 4 | |a gene expression | |
650 | 4 | |a genetics | |
650 | 4 | |a hypertension | |
650 | 4 | |a renin angiotensin system | |
650 | 4 | |a single-nucleotide polymorphism (SNP) | |
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650 | 4 | |a vasopressor agent | |
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700 | 1 | |a Sivankutty, Indu |e verfasserin |4 aut | |
700 | 1 | |a Jain, Sudhir |e verfasserin |4 aut | |
700 | 1 | |a Perla, Sravan Kumar |e verfasserin |4 aut | |
700 | 1 | |a Kumar, Ashok |e verfasserin |4 aut | |
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