Effect of Chromosome 19 Transfer on Blood Pressure in the Spontaneously Hypertensive Rat

Abstract

Abstract-Linkage studies in the spontaneously hypertensive rat (SHR) have suggested that a gene or genes regulating blood pressure may exist on rat chromosome 19 in the vicinity of the angiotensinogen gene. To test this hypothesis, we measured blood pressure in SHR progenitor and congenic strains that are genetically identical except for a segment of chromosome 19 containing the angiotensinogen gene transferred from the normotensive Brown Norway (BN) strain.Transfer of this segment of chromosome 19 from the BN strain onto the genetic background of the SHR induced significant decreases in systolic and diastolic blood pressures in the recipient SHR chromosome 19 congenic strain. To test for differences in angiotensinogen gene expression between the congenic and progenitor strains, we measured angiotensinogen mRNA levels in a variety of tissues, including aorta, brain, kidney, and liver. We found no differences between the progenitor and congenic strains in the angiotensinogen coding sequence or in angiotensinogen expression that would account for the blood pressure differences between the strains. In addition, no significant differences in plasma levels of angiotensinogen or plasma renin activity were detected between the 2 strains. Thus, transfer of a segment of chromosome 19 containing angiotensinogen from the BN rat into the SHR induces a decrease in blood pressure without inducing any major changes in plasma angiotensinogen levels or plasma renin activity. These results indicate that the differential chromosome segment trapped in the SHR chromosome 19 congenic strain contains a quantitative trait locus that influences blood pressure in the SHR but that this blood pressure effect is not explained by differences in plasma angiotensinogen levels or angiotensinogen expression. Key Words: hypertension, experimental Ⅲ angiotensinogen Ⅲ genetics Ⅲ blood pressure Ⅲ rats I n humans, linkage and association studies have suggested that a blood pressure (BP) regulatory gene exists in or near the angiotensinogen (Agt) gene on chromosome 1. [1][2][3] Linkage studies in the spontaneously hypertensive rat (SHR) also have suggested that at least 1 quantitative trait locus influencing BP exists on rat chromosome 19, which is homologous to human chromosome 1, in the vicinity of the Agt gene. 4,5 However, in a segregating population derived from strokeprone SHRs and normotensive Wistar-Kyoto (WKY) rats, no relationship was found between a polymorphism in the Agt gene and BP. 6 To investigate whether chromosome 19 plays a role in the greater BP of SHRs versus normotensive Brown Norway (BN) rats, we measured BP in an SHR progenitor strain and an SHR congenic strain that are genetically identical except for a segment of chromosome 19 that contains the Agt gene. To derive the SHR chromosome 19 congenic strain, we used backcross breeding combined with molecular selection to transfer the Agt gene and an associated segment of chromosome from the BN strain onto the genetic background of the SHR. We found that transfer of this segment of ...

Dissection of Chromosome 18 Blood Pressure and Salt-Sensitivity Quantitative Trait Loci in the Spontaneously Hypertensive Rat

“…Our results showed that the SHR-18 congenic strain has pronounced salt resistance, a characteristic not shown in other SHR congenic strains 10,13–17 . The effects of chromosome 18 on salt sensitivity do not appear to be related to salt intake or fluid consumption as these were found to be similar in SHR-18 and the SHR progenitor strain.…”

Exclusion of angiotensinogen gene in molecular basis of human hypertension: Sibpair linkage and association analyses in Australian Anglo-Caucasians

“…Thus there is no logical reason why a genetically determined elevation in plasma angiotensinogen in hypertension might play a role in the etiology of this condition. Finally, recent congenic experiments involving a sponaneously hypertensive rat chromosomal segment containing the angiotensinogen gene have shown that even though there is a quantitative locus for blood pressure in this region, this is not explained by differences in angiotensinogen expression or plasma concentrations [St Lezin et al, 1999].…”

Seven Lessons From Two Candidate Genes in Human Essential Hypertension

“…59 Lastly, transfer of a segment of chromosome 19 that contains the AGT gene from the normotensive Brown Norway rat into SHR induced a blood pressure decrease, but the role of AGT itself was ruled out. 60 These studies on SHR suggest that AGT is not a major genetic contributor to their hypertension.…”