Exon-I is involved in positive as well as negative regulation of human angiotensinogen gene expression

Abstract

Angiotensinogen is the glycoprotein precursor of one of the most potent vasoactive hormones, angiotensin-II. Angiotensinogen gene is primarily expressed in the liver, and this gene locus is linked with human essential hypertension. We show here that a mutation in exon-I reduces the basal expression of the human angiotensinogen gene in liver cells. We also show that a nucleotide sequence in exon-I binds to liver-enriched transcription factor HNF-3 and a ubiquitous factor AP4. Our studies also show that transient transfection of an expression vector containing AP4 coding sequence downregulates the expression of reporter constructs containing human angiotensinogen gene promoter. By contrast, co-transfection of an expression vector containing HNF-3beta coding sequence increases the expression of these reporter constructs. The human angiotensinogen gene has a C/A polymorphism located at -20, and we have shown that estrogen receptor-alpha binds to this sequence when nucleoside A is present at this site. We show here that co-transfection of an expression vector containing AP4 coding sequence reduces estrogen-induced promoter activity of reporter constructs containing human angiotensinogen gene promoter (with nucleoside A at -20) attached to the CAT gene. These studies partly explain the molecular mechanisms involved in tissue-specific expression of the human angiotensinogen gene.