Key result
Knockdown of USF1 reduced hAGT expression in female but not male mice, and reduced systolic blood pressure in female mice fed a high-fat diet, indicating sex-specific mechanisms in AGT regulation.
Both USF1 and USF2 are essential for angiotensinogen transcriptional regulation, involving distinct sex-specific and tissue-specific mechanisms in vivo.
USF1 effects in female mice do not inform hypertension care; extends evidence for sex-specific AGT transcriptional control.
A single-nucleotide polymorphism (C/A) located within an E-box at the -20 position of the human angiotensinogen (AGT) promoter may regulate transcriptional activation through differential recruitment of the transcription factors upstream stimulatory factor (USF) 1 and 2. To study the contribution of USF1 on AGT gene expression, mice carrying a (-20C) human AGT (hAGT) transgene were bred with mice harboring a USF1 gene trap allele designed to knock down USF1 expression. USF1 mRNA was reduced relative to controls in liver (9 ± 1%), perigenital adipose (16 ± 3%), kidney (17 ± 1%), and brain (34 ± 2%) in double-transgenic mice. This decrease was confirmed by electrophoretic mobility shift assay. Chromatin immunoprecipitation analyses revealed a decrease in USF1, with retention of USF2 binding at the hAGT promoter in the liver of male mice. hAGT expression was reduced in the liver and other tissues of female but not male mice. The decrease in endogenous AGT expression was insufficient to alter systolic blood pressure at baseline but caused reduced systolic blood pressure in female USF1 gene trap mice fed a high-fat diet. Treatment of USF1 knockdown males with intravenous adenoviral short hairpin RNA targeting USF2 resulted in reduced expression of USF1, USF2, and hAGT protein. Our data from chromatin immunoprecipitation assays suggests that this decrease in hAGT is attributed to decreased USF2 binding to the hAGT promoter. In conclusion, both USF1 and USF2 are essential for AGT transcriptional regulation, and distinct sex-specific and tissue-specific mechanisms are involved in the activities of these transcription factors in vivo.
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Park et al. (2012) studied Angiotensinogen expression and blood pressure regulation. USF1 gene trap allele (knockdown of USF1 expression) vs. Controls was evaluated on USF1 mRNA expression, hAGT expression, and systolic blood pressure. Knockdown of USF1 reduced hAGT expression in female but not male mice, and reduced systolic blood pressure in female mice fed a high-fat diet, indicating sex-specific mechanisms in AGT regulation.
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