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VASCULAR BIOLOGY

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

Department of Pathology, New York Medical College, Valhalla, New York

Submitted 11 August 2006 ; accepted in final form 26 April 2007

Angiotensinogen (AGT) is the precursor of one of the most important vasoactive hormone angiotensin II and this gene locus is associated with human essential hypertension. AGT is an acute phase protein and its gene expression is regulated by IL-6. Previous studies have identified three potential STAT-3 binding sites (APREs) located between –160 and –280 of the hAGT gene promoter but only APRE-1 (located between –271 and –279) was shown to be a bonafide enhancer for IL-6-induced promoter activity. We show here that APRE-2, located between –236 and –247, is indeed an HNF-1-binding site and plays an important role in basal and IL-6 induced promoter activity of this gene. Our chromatin immunoprecipitation (ChIP) assay shows that HNF-1 binds to this region of the hAGT gene promoter and its recruitment is increased in the presence of IL-6 in Hep3B cells. We also show that the promoter activity of a deletion construct containing only 223 bp of the hAGT gene promoter (that contains only APRE-3) is increased after IL-6 treatment. Our ChIP assay shows that IL-6 treatment recruits STAT-3 to APRE-3 and suggests that this is also an IL6 responsive element. We have previously shown that GR binds to the proximal promoter of the hAGT gene. Since GR physically interacts with STAT-3, we propose that transcription factors GR, STAT-3, and HNF-1 that bind to the nucleotide sequence located between –160 and –280 of the hAGT gene promoter are responsible for IL-6 induced promoter activity of this gene.

hypertension; inflammation; STAT-3 binding sites; chromatin immunoprecipitation; transcription

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