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(Hypertension. 1998;31:373.)
© 1998 American Heart Association, Inc.

Scientific Contributions

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

Elizabeth St. Lezin; Weizhong Liu; Ning Wang; Jia-Ming Wang; Vladimir Kren; Vaclav Zidek; Miroslava Zdobinska; Drahomira Krenova; Anita Bottger; Bert F. M. van Zutphen; Michal Pravenec

From the Department of Laboratory Medicine, University of California, San Francisco, Calif. (E.S., W. L., N. W., J.-M. W.); the Institute of Biology, 1st Medical Faculty, Charles University, Prague, Czech Republic (V.K., D.K., M.P.); the Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic (V.K., V.Z., M.Z., M.P.); and the Department of Laboratory Animal Science, Veterinary Faculty, University of Utrecht, Utrecht, Netherlands (A.B., B.F.M. v Z.)

Correspondence to Elizabeth St. Lezin, MD, Department of Laboratory Medicine, UCSF/Mt. Zion Medical Center 1613, PO Box 7921, San Francisco, CA 94120. E-mail stlezin{at}pangloss.ucsf.edu

	Abstract

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To investigate whether molecular variation in the renin gene contributes to the greater blood pressure of spontaneously hypertensive rats (SHR) versus normotensive Brown Norway (BN) rats, we measured blood pressure in an SHR progenitor strain and an SHR congenic strain that are genetically identical except at the renin gene and an associated segment of chromosome 13 transferred from the BN strain. Backcross breeding and molecular selection at the renin locus were used to create the SHR congenic strain (designated SHR.BN-Ren) that carries the renin gene transferred from the normotensive BN strain. We found that transfer of the renin gene from the BN strain onto the genetic background of the SHR did not decrease blood pressure in rats fed either a normal or high-salt diet. In fact, the systolic blood pressures of the SHR congenic rats tended to be slightly greater than the systolic blood pressures of the SHR progenitor rats. However, the congenic strain exhibited lower serum high-density lipoprotein cholesterol, and greater levels of total cholesterol, very-low-density lipoprotein, and intermediate-density lipoprotein cholesterol during administration of a high-fat, high-cholesterol diet. These findings demonstrate that (1) under the environmental circumstances of the current study, the greater blood pressure of SHR versus BN rats cannot be explained by strain differences in the renin gene and (2) a quantitative trait locus affecting lipid metabolism exists on chromosome 13 within the transferred chromosome segment. The SHR.BN-Ren congenic strain may provide a useful new animal model for studying the interaction between high blood pressure and dyslipidemia in cardiovascular disease.

Key Words: hypertension • cholesterol • genetics • congenic • quantitative trait locus • renin • rat

Abbreviations: BN = Brown Norway • HDL = high-density lipoprotein • IDL = intermediate-density lipoprotein • LDL = low-density lipoprotein • PCR = polymerase chain reaction • QTL = quantitative trait locus • RI = recombinant inbred • SHR = spontaneously hypertensive rat(s) • VLDL = very-low-density lipoprotein

	Introduction

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Linkage studies in the SHR have suggested that QTLs influencing blood pressure and lipid phenotypes might be linked on several chromosomes. For example, previous studies in RI and congenic strains derived from SHR and BN rats have demonstrated the presence of QTLs regulating blood pressure and lipid phenotypes on chromosomes 8, 19, and 20.¹ In the SHRxBN RI strains, we have also observed cosegregation between blood pressure and the renin gene on chromosome 13,² as well as a suggestive association (P<.004) between the D13Cebr9s3 marker (which maps close to Ren) and a serum subfraction of HDL cholesterol (M.P., 1997, unpublished observation). Other linkage studies in the SHR as well as the Dahl salt-sensitive rat have suggested that a QTL influencing blood pressure might exist on rat chromosome 13 in or near the renin gene.^3–5

To investigate whether molecular variation in the renin gene contributes to the greater blood pressure of SHR versus normotensive BN rats, we measured blood pressure in an SHR progenitor strain and an SHR congenic strain that are genetically identical except at the renin gene and an associated segment of chromosome 13 transferred from the BN strain. A secondary objective was to determine whether a QTL or QTLs influencing lipid phenotypes might exist in or near the renin gene on chromosome 13. To accomplish these objectives, we replaced the SHR chromosome 13 segment that contains the renin gene with the corresponding chromosome region from the normotensive BN rat. We found that transfer of the renin gene from the BN strain onto the genetic background of the SHR did not decrease blood pressure in rats fed either a normal or a high-salt diet. If anything, the systolic blood pressures of the SHR congenic strain carrying the BN renin allele tended to be slightly greater than the systolic blood pressures of the SHR progenitor strain. During administration of a high-fat, high-cholesterol diet, the SHR congenic strain carrying the chromosome 13 segment transferred from the BN rat exhibited significantly lower levels of serum HDL₃ cholesterol, and higher levels of total cholesterol, VLDL, and IDL cholesterol when compared with the progenitor SHR strain. These findings indicate that a QTL affecting serum lipoprotein levels in response to high dietary fat intake exists on chromosome 13 in the rat. The current findings also indicate that strain differences in the renin gene are not sufficient to explain the greater blood pressure of SHR versus BN rats.

	Methods

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Strains
The SHR congenic strain was derived from a progenitor strain of SHR (SHR/Ola) descended from inbred SHR originally obtained from the National Institutes of Health. This progenitor strain of SHR is commercially available in Europe and has been maintained by brother x sister mating at the Czech Academy of Sciences in Prague for more than 15 years. The rats were in the F48 generation when the SHR colony was established in Prague. The results of DNA fingerprint and PCR microsatellite tests have confirmed that the SHR progenitor strain is highly inbred.^2,6,7

The SHR congenic strain was derived by a selective breeding protocol in which a segment of chromosome 13 from the normotensive BN/Cr strain was transferred onto the genetic background of the progenitor SHR. A microsatellite marker within the renin gene was used for selection of heterozygous carriers in each backcross generation. After 10 generations of selective backcrossing to the SHR progenitor strain, the renin gene was fixed and maintained in the homozygous state by brother x sister mating and selective inbreeding of the offspring. This strain was designated SHR.BN-Ren.

Chromosome 13 Mapping
Renin genotyping was performed either by using PCR primers amplifying a polymorphic HindIII site in the fifth intron of the renin gene^8,9 or by amplifying the CT microsatellite marker D13UW1 (Renaa) within the gene.¹⁰ To determine the length of the differential chromosome 13 segment transferred onto the SHR genetic back-ground, we typed the congenic strain using the following markers polymorphic between the SHR and BN progenitor strains: D13Mgh1, D13Mgh2, D13Mgh3, D13Mgh4, D13Mgh5, D13Mgh7, D13Mgh8, D13Mit1, D13Mit2, D13Mit3, D13Mit4, D13Mit5, D13N1,¹¹ and Syt2.¹¹ Unless otherwise specified, primers were obtained from Research Genetics with sequences as published by Jacob et al.¹⁰ We found that the size of the homozygous BN chromosome fragment transferred was 2.5 cM, estimated from the map distances of Jacob et al¹⁰ and Remmers et al¹¹ (see Fig 1).

View larger version (12K): [in this window] [in a new window]   Figure 1. Linkage map showing the transferred segment of chromosome 13 in the SHR.BN-Ren congenic strain. The solid bar denotes the homozygous chromosome region transferred from the BN strain; the open regions denote the flanking segments of SHR chromosome. The shaded regions indicate regions of heterozygosity on either side of the transferred BN segment. The position of the D13Cerb9s3 marker is according to the map derived from the SHRxBN RI strains.15

Genotype Analysis of the SHR.BN-Ren Congenic Strain
The congenic status of the SHR.BN-Ren strain was confirmed by PCR analysis of the following markers polymorphic between the SHR and BN strains: D1Mit9, D1Mgh22, and D1Mit14 (chromosomel); D2Mgh11, D2Mit4, and D2Mit16 (chromosome 2); D3Mit5, D3Mit10, and D3Mit11 (chromosome 3); D4Mgh17, Eno2, and I16 (chromosome4); D5Mgh2, D5Mgh8, and D5Mit1 (chromosome 5); D6Mit8, D6Mit9, and Ighe (chromosome 6); D7Mgh11, D7Mit6, and D7Mit8 (chromosome7); Acaa, D8Mgh6, and D8Mit6 (chromosome8); D9Mit1, and D9Mit4 (chromosome9); D10Mgh8, D10Mit1, and D10Mit6 (chromosome 10); D11Mgh4, D11Mgh6, and D11Mit1 (chromosome 11); D12Mgh2, D12Mgh4, and D12Mit8 (chromosome 12); D14Mgh1, D14Mit1, D14Mit7, and D14Mit8 (chromosome 14); D15Mgh3, D15Mgh5, and D15Mit3 (chromosome 15); D16Mgh2, D16Mit2, and D16Mit3 (chromosome 16); D17Mit2, D17Mit4, and D17Mit7 (chromosome 17); D18Mgh1, D18Mit1, and D18Mit10 (chromosome 18); D19Mit2, D19Mit5, and D19Mit7 (chromosome 19); D20Mgh5 and D20UW1 (chromosome 20); and Arl, DXMgh1, and DXMit5 (chromosome X). PCR primers were obtained from Research Genetics or synthesized in the UCSF Biomolecular Resource Center according to published sequence.¹⁰

Cardiovascular Phenotyping
Pulsatile arterial pressures and heart rates were measured continuously in 15 male progenitor SHR and 12 male congenic SHR.BN-Ren rats for 10 to 11 weeks beginning at 10 weeks of age. Indwelling radiotelemetry transducers were implanted under ketamine/xylazine anesthesia and connected to catheters implanted in the lower abdominal aorta (Datasciences).^12,13 Systolic and diastolic blood pressures and heart rates were recorded in unanesthetized, unrestrained rats in 5-second bursts every 5 minutes during the day (6 AM to 6 PM) and night (6 PM to 6 AM). From these data, single 24-hour averages for systolic and diastolic blood pressure and heart rate were calculated for each rat at 10 to 14 weeks of age and 16 to 19 weeks of age.

From weaning through 14 weeks of age, all rats were given tap water ad libitum and fed a standard pelleted laboratory diet that contained 0.58% NaCl and 1.1% K. In a subset of six SHR progenitor and six SHR congenic rats, 1% NaCl was added to the drinking water for 1 week beginning at 14 weeks of age. These rats were then switched back to tap water for 3 weeks (ages 16 to 19 weeks). Blood pressures were measured again at age 20 weeks after a 2nd week of 1% NaCl water administration. The remaining nine SHR progenitor rats and six SHR congenic rats remained on tap water throughout the study. Twenty-four-hour average blood pressures were combined and analyzed by ANOVA for rats in both groups while on the normal salt diet at weeks 10 to 14 and 16 to 19 of age. Blood pressures of rats during 1% NaCl administration at 15 and 20 weeks of age were analyzed by ANOVA separately.

All procedures performed involving animals were in accordance with institutional guidelines.

Serum Lipid Phenotyping
From weaning until 7 weeks of age, a separate series of six SHR progenitor and six SHR.BN-Ren congenic rats were fed a commercial pelleted diet. After this baseline period, the rats were fed the commercial diet supplemented with 5% (wt/wt) olive oil and 2% (wt/wt) cholesterol for 4 weeks as previously described.^1,14

Lipid analysis was performed as described previously.¹ Total cholesterol and triglyceride levels were measured before and after the high-fat diet. Lipoprotein fractions were also measured after administration of the high-fat diet. Briefly, blood samples were obtained either from tail veins with the rats under light anesthesia or from the aorta at killing. Sera were cooled and kept at 4°C until ultracentrifugation. Lipoprotein fractions (VLDL, IDL, LDL, HDL₂, and HDL₃) were isolated by density gradient ultracentrifugation. Serum total cholesterol, triglyceride, and lipoprotein cholesterol concentrations in each fraction were determined using enzymatic test kits (Boehringer-Mannheim GmbH). Lipoprotein cholesterol concentrations were corrected for recovery. Between-strain differences in cholesterol, triglyceride, and lipoprotein cholesterol concentrations were analyzed using the Student’s t test and the Bonferroni correction. Statistical significance was defined as an adjusted value of P<.005.

	Results

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Genotype analysis of 59 widely dispersed polymorphic micro-satellite markers verified that the SHR.BN-Ren congenic strain differs from the SHR progenitor strain only in the vicinity of the renin gene. Analysis of markers on chromosome 13 revealed that the size of the segment transferred from the BN rat was 2.5 cM with an additional 16 cM region of heterozygosity (Fig 1).

The 24-hour average systolic and diastolic blood pressures of the SHR congenic rats carrying the renin gene transferred from the BN rat were not lower than the blood pressures of the SHR progenitor rats (Fig 2A and 2B). In fact, the 24-hour average systolic blood pressures of 10- to 14-week-old SHR.BN-Ren congenic rats tended to be slightly higher than the systolic blood pressures of the SHR progenitor rats (mean SBP±SEM, 171±0.9 mm Hg versus 167±1.4 mm Hg, P=.01). However, there were no significant differences in diastolic blood pressure or heart rate between the SHR progenitor rats and the SHR.BN-Ren congenic rats at 10 to 14 or 16 to 19 weeks of age. In addition, we found no difference in systolic or diastolic blood pressure between the SHR progenitor and SHR.BN-Ren congenic rats fed the high-salt diet, either at 15 or 20 weeks of age (data not shown). Addition of 1% NaCl to the drinking water increased systolic and diastolic blood pressures to the same extent in the progenitor and the congenic strains. There were no significant differences in cardiac mass between the progenitor and congenic strains (data not shown).

View larger version (14K): [in this window] [in a new window]   Figure 2. Twenty-four-hour average blood pressures determined by radiotelemetry in the SHR progenitor strain and the SHR.BN-Ren congenic strain. Each set of bars represents the 24-hour average blood pressures (mean±SEM) in the SHR progenitor strain (n=15) (solid bar) and SHR.BN-Ren congenic strain (n=12) (open bar) at 10–14 weeks of age or 16–19 weeks of age. Each bar represents approximately 1000 daytime and 1000 nighttime blood pressure measurements in each rat per week. A, Systolic blood pressure. The 24-hour average systolic blood pressures of the SHR.BN-Ren congenic rats were slightly higher than those of the SHR progenitor rats at 10–14 weeks of age. B, Diastolic blood pressure. The 24-hour average diastolic pressures of the SHR.BN-Ren congenic rats were not significantly different from those of the SHR progenitor rats.

Before administration of the high-fat, high-cholesterol diet, the SHR progenitor and the SHR.BN-Ren congenic strains showed similar total serum cholesterol and triglyceride levels (Table). The Table shows that after rats were fed the high-fat, high-cholesterol diet, the SHR.BN-Ren congenic strain showed significantly greater levels of serum total cholesterol (P<.005), VLDL (P<.0001), and IDL (P<.0001). The SHR.BN-Ren congenic strain also showed significantly lower levels of HDL₃ cholesterol (P<.0001) and a tendency for lower levels of HDL₂ cholesterol (P<.05).

View this table: [in this window] [in a new window]   Comparison of the SHR Progenitor with the SHR.BN-Ren Congenic Strain

	Discussion

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In genetic linkage studies using F2 and backcross populations derived from SHR and normotensive Lewis rats⁴ or SHR and Wistar-Kyoto rats,⁵ the renin allele inherited from the SHR progenitor strain was found to cosegregate with increased blood pressure. In RI strains derived from SHR and normotensive BN rats, the renin allele of the SHR also cosegregated with increased blood pressure.² In addition, in RI strains fed a high-fat, high-cholecterol diet, we detected a suggestive association (P<.004) between a serum subfraction of HDL cholesterol and the D13Cebr9s3 marker, which maps close to renin on chromosome 13. Taken together, these linkage studies suggest the possibility that QTLs affecting blood pressure and/or lipid metabolism might exist on chromosome 13 in the vicinity of the renin gene.

In the present study, we constructed a new congenic strain of SHR that carries the renin gene transferred from the BN rat. The SHR congenic strain is genetically identical to the progenitor SHR strain except for the renin gene and an associated segment of chromosome 13. We found that transfer of the renin allele from the normotensive BN rat onto the SHR background was not sufficient to decrease blood pressure in rats fed either a normal or high-salt diet. In fact, the blood pressure of the SHR.BN-Ren congenic strain tended to be higher than that of the SHR progenitor strain. However, transfer of this segment of chromosome 13 from the BN rat onto the SHR genetic background did induce a significant decrease in serum HDL cholesterol and an increase in serum total cholesterol, VLDL, and IDL cholesterol levels in rats fed a high-fat, high-cholesterol diet.

The current SHR.BN-Ren congenic strain was constructed to test the hypothesis that molecular differences in the renin gene contribute to the greater blood pressure of SHR versus BN rats. Given that the SD of our radiotelemetry blood pressure measurement is approximately 5 mm Hg, the current study had a 99% power of detecting a blood pressure difference of 10 mm Hg between the congenic and progenitor strains, and a 70% power of detecting a 5 mm Hg strain difference in blood pressure (assuming a two-tailed significance threshold of .05). Therefore, our blood pressure measurements in the congenic and progenitor strains indicate with reasonable certainty that molecular differences in the renin gene do not explain much, if any, of the greater blood pressure in the SHR versus BN strain. It is possible, however, that a chromosome 13 blood pressure QTL detected in previous linkage studies exists outside of the chromosome segment transferred in the SHR.BN-Ren congenic strain.

It should be noted that negative results obtained by comparing congenic and progenitor strains should be interpreted with caution. The possibility exists that a QTL on the differential chromosome segment may exhibit an effect on blood pressure only when in the presence of certain gene variants located in other regions of the genome. For example, although transfer of the BN renin gene itself did not affect blood pressure in the recipient congenic strain, transfer of the BN renin gene together with the BN angiotensinogen gene might reduce blood pressure. This possibility could be investigated by measuring blood pressure in an SHR double congenic strain in which both the SHR renin and angiotensinogen genes have been replaced by the corresponding BN genes.

In the current study, we demonstrate the existence of a QTL that affects lipid metabolism in the vicinity of the renin gene on chromosome 13. These results confirm our previous finding of a suggestive linkage between HDL levels and markers on chromosome 13 in the rat. Of interest, linkage studies in the mouse have suggested that a QTL influencing lipid metabolism exists on chromosome 1 in a region homologous to rat chromosome 13. In an F2 population derived from NZB/B1NJ and SM/J mice, Purcell-Huynh et al¹⁵ found linkage between markers on mouse chromosome 1 and levels of total cholesterol, triglycerides, and HDL cholesterol.¹⁵ Analysis of the corresponding region of mouse chromosome 1 may thus reveal important candidate genes that map to the region of rat chromosome 13 isolated in the SHR.BN-Ren congenic strain.

In the SHR.BN-Ren congenic strain, the chromosome segment transferred from the BN rat was associated with decreased HDL levels and increased cholesterol levels in response to a high-fat diet. Thus, the SHR.BN-Ren congenic strain represents a hypertensive model that is highly susceptible to dietary induced changes in serum lipids. Accordingly, this strain may provide a useful new animal model for studying the combined effects of high-blood pressure and dyslipidemia on susceptibility to stroke and other forms of target organ damage in hypertension.

	Acknowledgments

 
This work was supported by the Grant 96005 from the US-CZ Science and Technology program and from National Institutes of Health Program Project PO1 HL35018. The research of M.P. was supported in part by an International Research Scholar’s Award from the Howard Hughes Medical Institute. This work was also supported by a grant to E.S. from the California Affiliate of the American Heart Association.

Received September 17, 1997; first decision October 10, 1997; accepted October 24, 1997.

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