TA Repeat Variation, Npr1 Expression, and Blood Pressure

Abstract

Abstract-The activity of the atrial natriuretic peptide receptor (Npr1) is altered in spontaneously hypertensive rats (SHR) in relation to its mRNA levels, suggesting abnormal transcriptional control in hypertension. A single-stranded conformational polymorphism caused by a repetitive dinucleotide segment of 10 TA in BN-Lx and of 40 TA in SHR was localized at position Ϫ943 relative to the transcription start site of the Npr1 gene, downstream of a putative cGMP-regulatory region, and was the only sequence difference noted between the two strains. Transient transfections of Ϫ1520 to Ϫ920 Npr1 promoter-SV40-luciferase fusion vector showed that the construct from BN-Lx stimulated the SV40 promoter, whereas that from SHR slightly inhibited it. In contrast to the BN-Lx construct, the activity of the SHR fragment was refractory to downregulation by atrial natriuretic peptide. Genotype-phenotype correlation studies in recombinant inbred strains (RIS) derived from BN-Lx and SHR crosses revealed significant correlations of the TA repeat with basal guanylyl cyclase activity and Npr1 mRNA levels. The correlations were heightened by a locus on chromosome 10 containing the Ace gene. The highest basal guanylyl cyclase activity and Npr1 mRNA values were found in RIS with both genes (Npr1/Ace) of BN genotypes, whereas the lowest were recorded in RIS, with the SHR genotypes at both loci. This was inversely correlated with diastolic blood pressure in these strains. In conclusion, the longer TA repeat unit in the promoter of Npr1 of SHR, in tandem with a putative cGMP responsive element, regulates the transcription of the Npr1 gene with consequences on diastolic blood pressure.

Interactive Roles of Ets-1, Sp1, and Acetylated Histones in the Retinoic Acid-dependent Activation of Guanylyl Cyclase/Atrial Natriuretic Peptide Receptor-A Gene Transcription

“…Earlier studies have demonstrated a significant association of Npr1 gene variants with hypertensive family history, left ventricular mass index, and left ventricular septal wall thickness in human essential hypertension (14,15). It has also been shown that a longer thymine adenine repeat unit in spontaneously hypertensive rats regulates the transcription of the Npr1 gene, thus affecting diastolic blood pressure (16). Little is known about transcriptional regulation of the Npr1 gene, but the activity and expression of NPRA, assessed primarily through ANP-stimulated cGMP accumulation, are mediated by factors, including auto-regulation involving natriuretic peptides and other hormones (17)(18)(19)(20)(21)(22)(23)(24).…”

Genetic variation in the natriuretic peptide system and heart failure

“…They found that 5′ flanking region haplotypes were associated with up to a 2-fold difference in reporter expression [34]. Interestingly, this parallels rat model data where a length-repeat variant in the promoter region correlated with gene expression as well as diastolic BPs [39]. Consistent with this line of evidence is a study in humans, which showed that a microsatellite polymorphism in the 5′ flanking region was associated with cardiac hypertrophy among hypertensive patients [40].…”

Natriuretic Peptide Family: New Aspects

“…The activity of NPRA, or NPR1 for its gene designation, is altered in spontaneously hypertensive rats (SHR) and a single-stranded conformational polymorphism in NPR1 gene has been recently described [66] ANP has been found to be raised in essential hypertension [67], in pheochromocytoma [68], and in obesity-associated hypertension [69]. A potential role of ANP system in blood pressure control has been supported by data coming from molecular genetic studies.…”