Analysis of the Role of the SA Gene in Blood Pressure Regulation by Gene Targeting

Abstract

Abstract-The SA gene is expressed in the proximal tubule of the kidney and may be involved in blood pressure (BP) regulation. However, direct evidence for this is lacking. We constructed and analyzed an SA-null mouse in which exons 2 and 3 of the SA gene (including the start codon) had been deleted by homologous recombination. Basal BP and BP changes in response to increased salt and to treatment with losartan were compared between mice homozygous for the targeted SA allele (SA -/-mice) and littermates carrying the wild-type allele (SA ϩ/ϩ mice). Molecular and biochemical analysis confirmed the lack of SA gene product in SA -/-mice. SA -/-mice grew normally, were fertile, and had no overt phenotype. With both indirect and direct techniques, basal BP was similar in SA -/-and SA ϩ/ϩ mice. A high salt diet for 4 weeks caused a significant increase in BP in SA -/-and SA ϩ/ϩ , mice but there was no difference between the 2 strains. Losartan caused a significant decrease in BP, but again the response was similar between SA -/-and SA ϩ/ϩ mice, as were their kidney renin mRNA levels. SA is not involved in the regulation of either basal or salt related BP, and the lack of differential effect in SA -/-mice is not a consequence of compensatory activation of the renin-angiotensin system.

Locating a Blood Pressure Quantitative Trait Locus Within 117 kb on the Rat Genome

“…20 -23 However, the SA gene was eliminated as causative for a BP QTL on RNO1 by subsequent finer substitution mapping using congenic strains 24 -26 and using an SA knockout mouse. 27 The 117-kb BP QTL region on RNO9 represents 0.0043% of the rat genome, the total size of which is estimated at 2.75 Gb. 28 To date, this is the smallest region within which a BP QTL has been mapped.…”

Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes

“…24 -26 Recent rat congenic studies have not found support for the involvement of Sa in BP regulation. 27,28 Similarly, efforts to investigate the functional relationship of the Sa gene to BP using a mouse knock-out model were not fruitful, 29 although gene ablation is not a robust analogy of the increased allelic Sa gene expression in SHR.…”

SAH gene variants are associated with obesity-related hypertension in Caucasians: the PEGASE Study

“…Experimental data on different congenic rat strains [3][4][5], but not in SAH null mice [6], suggested that the SAH gene is associated with (salt-sensitive) hypertension, and a polymorphism at this locus appeared to determine the level of gene expression in the kidney and strongly co-segregated with increased blood pressure [7].…”