Role of C/A Polymorphism at −20 on the Expression of Human Angiotensinogen Gene

Abstract

Abstract-Angiotensinogen is the glycoprotein precursor of 1 of the most potent vasoactive hormones, angiotensin II.Human angiotensinogen gene contains a C/A polymorphism at Ϫ20 located between the TATA box and transcriptional initiation site. We show here that when nucleoside A is present at Ϫ20, this sequence binds to the estrogen receptor.We also show that transcriptional activity of reporter constructs containing human angiotensinogen gene promoter with nucleoside A at Ϫ20 is increased on cotransfection of an expression vector containing human estrogen receptor-␣ coding sequence in human hepatoma cells (HepG2) followed by estrogen treatment. On the other hand, adenoviral major late transcription factor binds preferentially to this region of the promoter when nucleoside C is present at Ϫ20. We also show that reporter constructs containing human angiotensinogen gene promoter with nucleoside C at Ϫ20 have increased basal promoter activity on transient transfection in HepG2 cells as compared with reporter constructs with nucleoside A at Ϫ20. Our data suggest that C/A polymorphism at Ϫ20 may modulate the expression of human angiotensinogen gene in a sex-specific manner. (Hypertension. 1999;33:108-115.)Key Words: angiotensinogen Ⅲ genes Ⅲ polymorphism Ⅲ estrogen Ⅲ gene regulation Ⅲ regulation, hormonal Ⅲ major late transcription factor T he renin-angiotensin system plays an important role in the regulation of blood pressure, fluid balance, and electrolyte homeostasis. Angiotensin II, which is 1 of the most potent vasoactive hormones, is obtained from its precursor molecule, angiotensinogen, by the combined proteolytic action of renin and angiotensin-converting enzyme. Angiotensinogen is primarily synthesized in the liver, although recent studies have shown that its mRNA is also present in fat, brain, kidney, heart, and aorta of rats 1 and humans.2 Because plasma concentration of angiotensinogen is close to the Michaelis constant of the enzymatic reaction between renin and angiotensinogen, 3 a rise or fall in plasma angiotensinogen levels can lead to a parallel change in the formation of angiotensin II, and an increase in plasma angiotensin II may lead to hypertension. Previous studies have shown a highly significant correlation between plasma concentrations of angiotensinogen and blood pressure, 4 higher plasma angiotensinogen concentrations in hypertensive parents and their offspring, 5 and elevations of blood pressure in transgenic animals overexpressing the angiotensinogen gene. 6,7 Recent studies have suggested that the angiotensinogen gene locus is involved in human essential hypertension 8 and pregnancy-induced hypertension. 9Human angiotensinogen gene contains a C/A polymorphism at Ϫ20 located between the TATA box and transcriptional initiation site. 8 We show here that this region of the promoter binds to estrogen receptor-␣ when nucleoside A is present at Ϫ20. We also show that a reporter construct, pHAG1.2CAT (Ϫ20A), is transactivated by cotransfection of the mammalian expression vector pSG5 containing th...

AGT A-20C (rs5050) gene polymorphism and ulcer occurrence in patients treated with low-dose aspirin: a case-control study / Polimorfismul AGT A-20C și ulcerele gastro-duodenale la pacienții sub tratament cu aspirină în doze antiagregante: studiu caz-control

“…It has been previously demonstrated that the C allele of the AGT A-20C gene polymorphism (rs5050) is associated with an increased AGT production according to genotype (AA < AC < CC) and its plasmatic concentration is progressively higher [14]. Recent studies in this respect started with the observation that co-treatments with ARB are correlated with a decreased number of ulcer in patients treated with LDA [15].…”

Identification of estrogen-responsive genes based on the DNA binding properties of estrogen receptors using high-throughput sequencing technology

“…However, among them, only a small number have been shown to possess functional EREs within the transcription regulatory region. In mammals, these genes include transcription factors, such as JUN [32] , FOS [33] , PGR [34] , and TP53 [35] , intracellular signaling molecules, such as HRAS [36] , BCL2 [37] , and BRCA1 [38] , enzymes, such as CHAT [39] , NQO1 [40] , and CKB [41] , secreted proteins, such as LTF [42] , SCGB1A1 [43] , OVGP1 [44] , C3 [45] , and AGT [46] , hormones, such as LHB [47] , OXT [48] , PRL [49] , and AVP [50] , membrane proteins, such as SNAT2 [51] and VEGFA [52] , the motogen TFF1 [53] , and the protease CTSD [54] . These genes are assumed to directly mediate various estrogen actions in normal tissues, as well as in cancer and other diseases.…”

Genetics of arterial hypertension and hypotension

“…Many additional polymorphisms, however, have been identified in the AGT gene, including an additional promoter polymorphism at −20. This polymorphism is also interesting, since depending on the genotype different response elements are generated, including those for estrogen receptor α, upstream regulatory factor and members of the COUP-TF family, which correlates with different phenotypes, including pregnancydependent variations in AGT levels, non-modulating hypertension and an altered relationship between BMI and blood pressure (Zhao et al 1999;Morgan et al 2000;Hilgers et al 2001;Tiago et al 2002). Current research efforts address the haplotype structure of the AGT gene, which should be comparatively easy given the short length of the gene of only ∼12 kb.…”