Effect of Renin Gene Transfer on Blood Pressure in the Spontaneously Hypertensive Rat

Lezin, Elizabeth St.; Liu, Weizhong; Wang, Ning; Wang, Jiaming; Křen, Vladimı́r; Zidek, Vaclav; Zdobinská, M; Křenová, D; Bottger, A.; Zutphen, Bert F. M. Van; Pravenec, Michal

doi:10.1161/01.hyp.31.1.373

Cited by 16 publications

(7 citation statements)

References 15 publications

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“…We have bred congenic rats to isolate predisposing genes and to determine whether obesity, type II diabetes and other clinical phenotypes of the OLETF strain might be treatable by partially correcting one of their multiple defects (St Lezin et al, 1998). In this study, we describe congenic rats carrying a Dmo1 allele from the non-obese and non-diabetic F344 rat in the context of the OLETF background.…”

Section: Discussionmentioning

confidence: 99%

Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain

et al. 2001

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Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.

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Section: Discussionmentioning

confidence: 99%

Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain

et al. 2001

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“…Previous attempts [34][35][36][37][38][39][40][41][42] at isolating blood pressure QTLs in congenic strains have mostly, apart from a few exceptions, 34 -35 involved transferring the region in a single direction. In the majority of cases, this has been from the normotensive strain into the hypertensive strain, on the assumption that demonstrating a decrease in blood pressure would be easier than an increase.…”

Section: Discussionmentioning

confidence: 99%

Successful Isolation of a Rat Chromosome 1 Blood Pressure Quantitative Trait Locus in Reciprocal Congenic Strains

et al. 1998

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Abstract-Linkage analyses in experimental crosses of hypertensive and normotensive rats have strongly suggested the presence of a quantitative trait locus (QTL) influencing blood pressure on rat chromosome 1, at or near the Sa gene. To confirm the presence of such a locus and move toward identification of the causative gene, we have developed, through targeted breeding over 10 generations using an Sa gene polymorphism to select breeders at each generation, 2 congenic strains, 1 containing a segment of spontaneously hypertensive rat (SHR) chromosome 1 in a Wistar-Kyoto rat (WKY) genetic background (WKY.SHR-Sa), and the other a segment of WKY chromosome 1 in an SHR background (SHR.WKY-Sa). WKY.SHR-Sa contains at least Ϸ26 cM of SHR chromosome 1, between markers mD7mit206 and D1Mit2 (and including the SHR allele of the Sa gene), and SHR.WKY-Sa carries at least Ϸ15 cM of WKY chromosome 1, between mD7mit206 and D1Wox34 (and including the WKY allele of the Sa gene). Blood pressure of WKY.SHR-Sa rats measured at 16, 20, and 25 weeks of age was significantly higher than that of WKY, whereas blood pressure of SHR.WKY-Sa rats was significantly lower than that of SHR. At 25 weeks, the mean differences in systolic and diastolic blood pressure between WKY.SHR-Sa and WKY were ϩ11.5 mm Hg (Pϭ0.001) and ϩ11.6 mm Hg mm Hg (PϽ0.001), respectively. The corresponding differences between SHR.WKy-Sa and SHR were Ϫ11.3 mm Hg (Pϭ0.002) and Ϫ9.1 mm Hg (Pϭ0.005), respectively. The differences represent about one fifth of the blood pressure difference between SHR and WKY. Renal Sa mRNA levels in the congenic strains reflected their Sa allele with a high level in WKY.SHR-Sa and a low level in SHR.WKY-Sa, consistent with previous data suggesting that the level of Sa expression is primarily determined by cis-acting elements in or near the Sa gene. Our results show that we have successfully isolated a major rat chromosome 1 blood pressure QTL located in the vicinity of the Sa gene in reciprocal congenic strains derived from SHR and WKY. The strains can now be used to further define the region containing the QTL and also to characterize intermediary mechanisms through which the QTL influences blood pressure. In addition, comparison of the regions introgressed in our congenic strains with the location of the peak LOD score for chromosome 1 blood pressure QTL in second filial generation progeny derived from our SHRϫWKY cross suggests that there may be at least 1 further QTL influencing blood pressure on this rat chromosome. (Hypertension. 1998;32:639-646.)

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“…For example, we found no major differences in systolic or diastolic BP between the SHR strain and SHR congenic strains carrying segments of chromosomes 13 or 20 transferred from the BN rat. 7,20 To investigate whether replacing the Agt gene in the SHR with the Agt gene from the normotensive BN rat would affect Agt expression, plasma Agt levels as well as BP, we measured plasma levels of Agt and tissue-specific Agt expression in SHR and SHR.BN-Agt congenic rats. We found no differences in plasma Agt levels or PRA that could account for the BP differences observed between the progenitor and congenic SHRs.…”

Section: Discussionmentioning

confidence: 99%

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

Lezin

Zhang²,

Yang³

et al. 1999

Hypertension

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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 ...

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Effect of Renin Gene Transfer on Blood Pressure in the Spontaneously Hypertensive Rat

Cited by 16 publications

References 15 publications

Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain

Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain

Successful Isolation of a Rat Chromosome 1 Blood Pressure Quantitative Trait Locus in Reciprocal Congenic Strains

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

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