Journal
JOURNAL OF HYPERTENSION
Volume 20, Issue 12, Pages 2391-2398Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00004872-200212000-00018
Keywords
polymorphisms; gene regulation; renin-angiotensin system; tissue culture; human
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Background The production of renin, which catalyses the rate-limiting step of the renin-angiotensin system, is strongly stimulated by a 225 by enhancer element in the distal region of the promoter of the human gene (-5777 to -5552). Objective To demonstrate the major role played by this enhancer in decoy experiments, to identify variants in this region, and to determine their effects on renin gene transcription. Methods and results We used this element as a decoy for transcription factors in human choriodecidual cells. The activity of the renin gene promoter was inhibited by 95% in the presence of this 225 by enhancer element. This confirmation of the key role of this element: suggested that changes in this region would be likely to affect renin gene expression. We therefore sequenced 70 genomic DNAs to identify variations in this region. We identified two new single nucleotide polymorphisms (SNPs) downstream from the 225 by enhancer element at positions -5434 and -5312. We transfected choriodecidual cells with the four variants and found that a 592 by region (-5870 to -5312) including the 225 by element and the two SNPs had stronger enhancer activity than the 225 by element alone, and that levels of transcription were 45% greater with the -5312T variant than with the -5312C variant, whereas none of the -5434 variants had an effect on renin transcription. Cis-regulatory elements close to the -5312 variant were identified in gel mobility shift assays on the basis of specific interactions between human choriodecidual cell nuclear extracts and an oligonucleotide including this polymorphism. Conclusion This study demonstrates that the human renin enhancer not only comprises the 225 by element, but also extends to the region containing the -5312 SNP. (C) 2002 Lippincott Williams Wilkins.
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