HNF-1α plays an important role in IL-6-induced expression of the human angiotensinogen gene

Jain, Sudhir; Li, Yanna; Patil, Sai; Kumar, Ashok

doi:10.1152/ajpcell.00433.2006

Cited by 33 publications

(35 citation statements)

References 40 publications

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“…In addition to CEBP family members, NR3C1, STAT3, and HNF1A that bind to the nucleotide sequence located between −162 and −278 of the AGT promoter are involved in IL6-induced activation of AGT ( Figure S4A). 31 Because the AGT promoter was fully unmethylated in human liver HepG2 cells, we were unable to use these cells to analyze changes in DNA methylation ( Figure S2). Instead, we used human adrenocortical H295R cells that had a partially methylated AGT promoter (Figure 2A).…”

Section: Discussionmentioning

confidence: 99%

Dynamic CCAAT/Enhancer Binding Protein–Associated Changes of DNA Methylation in the Angiotensinogen Gene

et al. 2014

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A ngiotensinogen (AGT; serpin peptidase inhibitor, clade A, member 8) is a glycoprotein that is the primary substrate of the renin-angiotensin-aldosterone system (RAAS) and is, therefore, one of the most frequently studied proteins because of its contributions to hypertension. Given that AGT is the primary substrate controlling the rate-limiting step of the production of angiotensin peptides, a rise in AGT levels can lead to a parallel increase in the formation of the physiologically active enzyme angiotensin II and may ultimately result in multiple diseases, such as hypertension, cardiovascular disease, and kidney injury. 1-3The AGT gene is expressed in many human tissues, as determined by an analysis of cDNA sequences available on the Unigene website. The AGT gene is known to be highly expressed in the liver, heart, and brain, whereas weakly expressed in the adrenal gland (www.ncbi.nlm.nih.gov/ sites/entrez?db=unigene; Figure S1 in the online-only Data Supplement). The expression of AGT is under developmental and hormonal control in a cell type-specific manner. 4 It is generally approved that AGT expression is predominantly regulated at the transcriptional level. 5 Multiple cis-acting DNA regulatory elements and transcription factors are known to be important in the regulation of AGT. 4,[6][7][8][9] Among those transcription factors, CCAAT/enhancer binding protein (CEBP) has been shown to increase AGT promoter activity through binding to the promoter region 6 and is important for the regulation of AGT in response to interleukin 6 (IL6). 6,10 The CEBP family facilitates the binding of other transcription factors to shared sites and contributes to efficient chromatin remodeling at some of these sites. This feature of CEBP function indicates that it is a pioneering factor for the assembly of transcription factor complexes at these sites. 11Abstract-DNA methylation patterns are maintained in adult somatic cells. Recent findings, however, suggest that all methylation patterns are not preserved. We demonstrate that stimulatory signals can change the DNA methylation status at a CCAAT/enhancer binding protein (CEBP) binding site and a transcription start site and activate expression of the angiotensinogen gene (AGT). A CEBP binding site in the human AGT promoter was hypomethylated in tissues with high expression of AGT, but not in those with low expression. The transcriptional activity of AGT promoter sequences cloned into a reporter plasmid depended on DNA methylation. In cultured human cells, interleukin 6 stimulation caused DNA demethylation around a CEBP binding site and a transcription start site; demethylation was accompanied by increased CEBP-β recruitment and chromatin accessibility of the AGT promoter. DNA methylation activity decreased in the nucleus. Excess circulating aldosterone upregulated AGT expression and was accompanied by DNA hypomethylation around a CEBP binding site and a transcription start site in human visceral adipose tissue. High salt intake led to upregulation of Agt expression, DNA hypometh...

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Section: Discussionmentioning

confidence: 99%

Dynamic CCAAT/Enhancer Binding Protein–Associated Changes of DNA Methylation in the Angiotensinogen Gene

et al. 2014

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“…The EMSA protocol was followed as described previously (22). Nuclear extracts for gel mobility shift assays were prepared by modification of a method described previously (23).…”

Section: Methodsmentioning

confidence: 99%

Transgenic Mice with −6A Haplotype of the Human Angiotensinogen Gene Have Increased Blood Pressure Compared with −6G Haplotype

Jain

Tillinger

Pandey

et al. 2010

Journal of Biological Chemistry

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Hypertension is a serious risk factor for cardiovascular disease, and the angiotensinogen (AGT) gene locus is associated with human essential hypertension. The human AGT (hAGT) gene has an A/G polymorphism at ؊6, and the ؊6A allele is associated with increased blood pressure. However, transgenic mice containing 1.2 kb of the promoter with ؊6A of the hAGT gene show neither increased plasma AGT level nor increased blood pressure compared with ؊6G. We have found that the hAGT gene has three additional SNPs (A/G at ؊1670, C/G at ؊1562, and T/G at ؊1561). Variants ؊1670A, ؊1562C, and ؊1561T almost always occur with ؊6A, and variants ؊1670G, ؊1562G, and ؊1561G almost always occur with ؊6G. Therefore, the hAGT gene may be subdivided into either ؊6A or ؊6G haplotypes. We show that these polymorphisms affect the binding of HNF-1␣ and glucocorticoid receptor to the promoter, and a reporter construct containing a 1.8-kb hAGT gene promoter with ؊6A haplotype has 4-fold increased glucocorticoid-induced promoter activity as compared with ؊6G haplotype. In order to understand the physiological significance of these haplotypes in an in vivo situation, we have generated double transgenic mice containing either the ؊6A or ؊6G haplotype of the hAGT gene and the human renin gene. Our ChIP assay shows that HNF-1␣ and glucocorticoid receptor have stronger affinity for the chromatin obtained from the liver of transgenic mice containing ؊6A haplotype. Our studies also show that transgenic mice containing ؊6A haplotype have increased plasma AGT level and increased blood pressure as compared with ؊6G haplotype. Our studies explain the molecular mechanism involved in association of the ؊6A allele of the hAGT gene with hypertension.

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“…), or a consensus binding sequence for HNF1 (HNF1 cons.) (Jain et al, 2007). (B) Luciferase reporter gene assay of Huh7 cells overexpressing the HNF1a or HNF1b isoforms.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Nuclear Factor 1 Regulates the Expression of the Organic Cation Transporter 1 via Binding to an Evolutionary Conserved Region in Intron 1 of the OCT1 Gene

O’Brien

Bokelmann

Ramı́rez

et al. 2013

J Pharmacol Exp Ther

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The organic cation transporter 1 (OCT1), also known as solute carrier family 22 member 1, is strongly and specifically expressed in the human liver. Here we show that the hepatocyte nuclear factor 1 (HNF1) regulates OCT1 transcription and contributes to the strong, liver-specific expression of OCT1. Bioinformatic analyses revealed strong conservation of HNF1 binding motifs in an evolutionary conserved region (ECR) in intron 1 of the OCT1 gene. Electrophoretic mobility shift and chromatin immunoprecipitation assays confirmed the specific binding of HNF1 to the intron 1 ECR. In reporter gene assays performed in HepG2 cells, the intron 1 ECR increased SV40 promoter activity by 22-fold and OCT1 promoter activity by 13-fold. The increase was reversed when the HNF1 binding sites in the intron 1 ECR were mutated or the endogenous HNF1a expression was downregulated with small interfering RNA. Following HNF1a overexpression in Huh7 cells, the intron 1 ECR increased SV40 promoter activity by 11-fold and OCT1 promoter activity by 6-fold. Without HNF1a overexpression, the increases were only 3-and 2-fold, respectively. Finally, in human liver samples, high HNF1 expression was significantly correlated with high OCT1 expression (r 5 0.48, P 5 0.002, n 5 40). In conclusion, HNF1 is a strong regulator of OCT1 expression. It remains to be determined whether genetic variants, disease conditions, or drugs that affect HNF1 activity may affect the pharmacokinetics and efficacy of OCT1-transported drugs such as morphine, tropisetron, ondansetron, tramadol, and metformin. Beyond OCT1, this study demonstrates the validity and usefulness of interspecies comparisons in the discovery of functionally relevant genomic sequences.

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HNF-1α plays an important role in IL-6-induced expression of the human angiotensinogen gene

Cited by 33 publications

References 40 publications

Dynamic CCAAT/Enhancer Binding Protein–Associated Changes of DNA Methylation in the Angiotensinogen Gene

Dynamic CCAAT/Enhancer Binding Protein–Associated Changes of DNA Methylation in the Angiotensinogen Gene

Transgenic Mice with −6A Haplotype of the Human Angiotensinogen Gene Have Increased Blood Pressure Compared with −6G Haplotype

Hepatocyte Nuclear Factor 1 Regulates the Expression of the Organic Cation Transporter 1 via Binding to an Evolutionary Conserved Region in Intron 1 of the OCT1 Gene

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