title: TA repeat variation, Npr1 expression, and blood pressure: impact of the Ace locus.
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 -943 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 -1520 to -920 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.
authors.affiliation: Laboratory of Cellular Biology of Hypertension, Centre de recherche du Centre hospitalier de l'Université de Montréal-Hôtel-Dieu, , Montréal, Québec, Canada. johanne.tremblay@umontreal.ca
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.forename: David H F
authors.initials: DH
authors.lastname: Hum
authors.forename: Rocio
authors.initials: R
authors.lastname: Sanchez
authors.forename: Pierre
authors.initials: P
authors.lastname: Dumas
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Drahomira
authors.initials: D
authors.lastname: Krenova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kren
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Kunes
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Pausova
authors.forename: Francis
authors.initials: F
authors.lastname: Gossard
authors.forename: Pavel
authors.initials: P
authors.lastname: Hamet
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D018900:Dinucleotide Repeats; D005786:Gene Expression Regulation; D005838:Genotype; D006162:Guanylate Cyclase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D017461:Receptors, Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D007703:Peptidyl-Dipeptidase A; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A