(Hypertension. 2001;37:456.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Brown Norway Chromosome 13 Confers Protection From High Salt to Consomic Dahl S Rat
From the Department of Physiology, Medical College of Wisconsin, Milwaukee.
Correspondence to Allen W. Cowley, Jr, PhD, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226-0509. E-mail cowley{at}mcw.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Consomic rats (SS.BN13), in which chromosome 13 from normotensive inbred Brown Norway rats from a colony maintained at the Medical College of Wisconsin (BN/Mcw) was introgressed into the background of Dahl salt-sensitive (SS/Mcw) rats, also maintained in a colony at the Medical College of Wisconsin, were bred. The present studies determined the mean arterial pressure (MAP) responses to salt and renal and peripheral vascular responses to norepinephrine and angiotensin II; 24-hour protein excretion and histological analyses were used to assess renal pathology in rats that received a high salt (4% NaCl) diet for 4 weeks. MAP of rats measured daily during the fourth week averaged 170±3.3 mm Hg in SS/Mcw rats, 119±2.1 mm Hg in SS.BN13 rats, and 103±1.3 mm Hg in BN/Mcw rats. After salt depletion, MAP fell an average of 27±4.5 mm Hg in SS/Mcw rats, 9±2.6 mm Hg in SS.BN13 rats, and 11±3.0 mm Hg in BN/Mcw rats. Protein excretion of SS/Mcw rats on a high salt diet averaged 189±30 mg/24 h, 63±18 mg/24 h in SS.BN13 rats, and 40±6.4 mg/24 h in BN/Mcw rats. Compared with SS.BN13 and BN/Mcw rats, SS/Mcw rats exhibited significantly greater increases of renal vascular resistance in response to intravenous norepinephrine and angiotensin II. Severe medullary interstitial fibrosis and tubular necrosis after a high salt diet were found consistently in SS/Mcw rat kidneys but were largely absent in the SS.BN13 and BN/Mcw rat kidneys. A similar degree of glomerular sclerosis was found in both SS/Mcw and SS.BN13 rats. In rats fed a 0.4% salt diet, the glomerular filtration rate of SS/Mcw rats was significantly less than that of BN/Mcw and SS.BN13 rats. These results reveal a powerful gene, or set of genes, within chromosome 13 of BN/Mcw rats that confers protection from the detrimental effects of high salt to the SS/Mcw rats.
Key Words: hypertension, sodium dependent • rats • sodium • chromosome 13 • blood pressure • consomic
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Dahl salt-sensitive (SS) rats exhibit many of the abnormalities that occur with hypertension in African Americans,1 2 including blood pressure salt sensitivity,3 4 insulin resistance,5 and hyperlipidemia.6 They have a low renin form of hypertension3 that is refractory to treatment with converting enzyme inhibitors7 8 and is effectively treated with diuretics.7 9 Moreover, these rats rapidly develop severe progressive hypertensive glomerulosclerosis that leads to end-stage renal disease, as is commonly also seen in African Americans with hypertension.9 10 For these reasons, insights and findings of the studies in SS rats may provide valuable clues to the genetic basis of hypertension and related traits in African Americans.
The explosion of genomic resources in the rat has led to remarkable advances in identifying the regions of the rat genome that contain blood pressure quantitative trait loci (QTLs), as reviewed by Hamet et al,11 Zicha and Kunes,12 and Rapp.13 We have recently completed a linkage analysis based on an intercross of SS and Brown Norway (BN) salt-insensitive rats in which total genome scans using 238 polymorphic markers, evenly distributed throughout the genome, were scored. All F2 rats (113 males and 99 females) were extensively phenotyped for 239 measured or derived traits. This linkage analysis indicated the existence of a broad range of traits related to pathways of functional importance in hypertension that mapped to 19 chromosomes.14 15 The development of congenic strains has been used by a number of laboratories, including our own, to confirm and narrow QTL regions of interest.16 17 Despite the usefulness of congenic rat models in the deconstruction of complex traits and the identification of candidate genes, this work has been hampered by the time and expense involved in producing these informative recombinant rats. Even with the use of marker-assisted selection to identify the rats best suited for backcrossing in generations,18 we have found that the process of developing an inbred congenic strain requires nearly 2 years and 5 to 7 generations of backcrosses to achieve rats that are sufficiently isogenic to make meaningful comparisons.
To overcome these limitations, we have been developing a
panel of 44 reciprocal consomic inbred rat strains. A consomic strain
is developed by introgression of an individual chromosome into the
genomic background of the recipient strain. Our consomic panels consist
of inbred Brown Norway rats maintained at the Medical College of
Wisconsin (BN/Mcw), whose chromosomes have been systematically
transferred into the genomic background of SS/Mcw rats, and vice versa.
Nadeau et al19 have reported
the generation of consomics or chromosomal substitution strains in
mice. Once a consomic line has been developed, which requires 7 to 8
backcrossed generations, congenic inbred strains can be obtained for
any region in 2 generations. A simple F2 cross between the consomic and
the parental (recipient) strain would then produce 
25% homozygous
congenic rats that can be inbred. A consomic rat can thereby be used to
generate congenic inbred strains within 6 months. The present study
presents the phenotyping results from our first completed consomic
rat line developed by introgression of chromosome 13, which carries the
renin gene, of the BN/Mcw rat into the genomic background of the SS/Mcw
rat.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Generation of Consomic Rats
The consomic rat line was derived by using inbred normotensive BN/SsNHsd/Mcw rats and salt-sensitive hypertensive Dahl SS/JrHsd/Mcw rats, referred to herein as BN/Mcw and SS/Mcw strains, whose origin has been described previously.14 Residual heterozygosity and genetic contamination were eliminated by using a set of 182 microsatellite markers (Research Genetics) for genotyping that provided even coverage of the 21 chromosomes (10-cM intervals). The progenitor rats used for the present study were homozygous for all regions tested, and each of these parental strains has since undergone a periodic total genome scan to ensure allelic homogeneity.
The generation of a panel of reciprocal consomic rats with the use of SS/Mcw and BN/Mcw rats was initiated by using a single F1 male, originating from a male SS/Mcw and a female BN/Mcw, backcrossed to 2 or 3 SS/Mcw and BN/Mcw females. For subsequent backcrosses, each selected male breeder was backcrossed to 3 to 6 parental females. DNA was extracted from tail tips of males and genotyped with markers spaced every 10 cM for the introgressed chromosome. Rats not heterozygous for the entire chromosome were culled. Remaining male progeny were genotyped by using a subset of genetic markers that characterized the mixed chromosomes from the previous generation to select the best next breeders. This iterative process was continued until there were no longer mixed chromosomes in the (recipient) genetic background. The rats carrying full-length heterozygous target chromosomes were crossed to fix the donor chromosome, and a total genome scan was performed to verify that the line was isogenic. The consomic line was then maintained by brother-sister matings.
Salt Diet and Surgical Preparation
Breeding animals were maintained on a 0.4% NaCl rat
chow diet (Dyets, Inc) because a lower salt diet impairs fertility.
Study rats were maintained on a 0.1% NaCl diet until 10 weeks of age
(until postnatal development of the kidney was complete) and then
switched to a high salt (4.0% NaCl) diet for 3 weeks before the study.
A femoral catheter was implanted during the third week of high salt
intake as described
previously,14 followed by a
5- to 7-day recovery period.
Arterial Pressure Measurements and
Urine Collection in Conscious Rats
All rats were housed individually in
metabolic cages, and arterial pressure was
measured daily for 3 hours as previously
described.14 Urine was
collected during the final 2 days of high salt intake to determine
daily urine volume, protein, and creatinine excretion, and
a 500-µL blood sample was collected for measurement of plasma
creatinine concentration and plasma renin activity (PRA).
After 3 days of blood pressure measurements during the "inactive"
light period with the rats on the high salt diet, an
intraperitoneal injection of furosemide (Lasix, 10
mg/kg) was administered, and rats were returned to a 0.4% salt intake.
Arterial pressure was measured again for 3 hours after 36
hours of salt depletion, and urine and blood samples were collected
again.
Arterial Pressure and RBF Responses
to Intravenous Infusion of Ang II and NE in
Anesthetized Rats
Rats that had undergone sodium depletion in the above
protocol were anesthetized with ketamine (30 mg/kg IP),
which was followed by
5-sec-butyl-5-ethyl-2-thiobarbituric
acid (Inactin, 30 mg/kg IP), and prepared for measurement of renal
blood flow (RBF) by using electromagnetic flowmetry as
described previously.20 A 1%
albumin solution in isotonic saline was infused at a rate in of
50 µL/min throughout the study. After a 30-minute equilibration
period, control measurements were made during a 15-minute control
period. Then, RBF and blood pressure responses to graded, 5-minute,
intravenous infusions of angiotensin II (Ang
II) were measured (20, 100, and 200 ng/kg per minute). After a
10-minute reequilibration period, the response to
intravenous infusions of norepinephrine (NE) at
0.5, 1.0, and 3.0 µg/kg per minute were measured. Pressure and flow
data reported in the present study represent the average of
the final 2 minutes of each 5-minute infusion.
Assessment of Glomerular
Injury
At the end of the study, the kidneys were removed and
immersion-fixed in 10% neutral buffered formalin and
paraffin-embedded, and sections were prepared and stained with PAS and
Masson’s trichrome stain, which highlights the fibrotic tissue.
Glomeruli (20 to 25 per slide) were evaluated (scored from 0 to 4) on
the basis of the degree of glomerulosclerosis
and mesangial matrix expansion as previously described by
Raij et al.21 The renal
medullae were also assessed for interstitial fibrosis and
tubular necrosis. The percentage of the outer medullary tissue that was
PAS positive in 20 randomly chosen frames per rat kidney was quantified
by using Metamorph Image Analysis software (version 4.0,
Universal Imaging Systems Corp). This percentage largely reflects outer
medullary tissue occupied by protein casts in necrotic thick ascending
limbs of Henle.
Measurement of GFR and Filtration
Fraction
Separate groups of the SS/Mcw, SS.BN13, and BN/Mcw
rats were used to determine glomerular filtration rate
(GFR), RBF (Transonic Systems Inc), and filtration fraction
(GFR/calculated renal plasma flow). The rats were maintained from birth
on a 0.4% salt intake and studied at 14±0.4 weeks of age. Rats were
anesthetized (30 mg/kg IP ketamine and 30 mg/kg IP
Inactin) and surgically prepared as described above for measurements.
GFR was determined by the clearance of
[3H]inulin as previously
described.20 Two 20-minute
urine collections were performed while arterial pressure
and RBF were continuously recorded. Urine flow rate was determined
gravimetrically. Sodium and potassium concentrations of urine and
plasma samples were measured by using a flame photometer (Corning 480,
Bayer Corp). Urinary excretion data, RBF, and GFR were factored per
gram kidney weight.
Statistical Analysis
Data are presented as mean±SE, with
significance determined by ANOVA followed by a least significant
difference multiple comparison test. The significance of differences
between the parental strain representing the genomic
background (SS/Mcw) and the consomic background (SS.BN13) was further
tested by an unpaired t test.
Ang II and NE dose responses were analyzed by 2-way
repeated-measures ANOVA, with the Tukey multiple comparison test. A
probability of P<0.05 for a
2-tailed test was considered significant (ANOVA, SigmaStat Inc, version
2.03).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Genotypic Validation of Consomic Rats
The consomic SS.BN13 rats that produced the progeny used in the present study were genotyped with the use of a total of 182 markers, spaced every 10 cM, giving an average of 10 to 15 markers on the longer chromosomes (chromosomes 1 to 10) and 6 to 10 markers on the shorter chromosomes (chromosomes 11 to 20 and X). Chromosome 13 was found to be homozygous BN at all marker sites. The remainder of the SS/Mcw genome exhibited, on average, 9.6% heterozygosity. None of these heterozygous markers fell into any of the 115 suggestive QTL regions that were mapped in the SS/Mcw X BN/Mcw F2 intercross study.
Blood Pressure and Renin Responses Before and
After Sodium Depletion in Unanesthetized Rats
As seen in
Figure 1, top, the transfer of BN/Mcw chromosome 13 into the
SS/Mcw genomic background had a profound effect on the mean
arterial pressure (MAP) as recorded during the fourth
week of the high salt diet. MAP averaged 170±3.3 mm Hg in SS/Mcw
rats, 119±2.1 mm Hg in SS.BN13 rats, and 103±1.3 mm Hg in
BN/Mcw rats.
|
P<0.05 vs SS/Mcw; 
P<0.05 vs SS.BN13.Figure 1, bottom, shows that the average reduction of MAP with salt depletion was significantly less in consomic SS.BN13 rats (9±2.6 mm Hg) than in SS/Mcw rats (27±4.5 mm Hg). MAP fell 11±3.0 mm Hg in BN/Mcw rats. Not shown are the PRA responses to sodium depletion, which only increased from 0.4±0.1 to 1.0±0.2 ng angiotensin I (Ang I)/mL per hour in SS/Mcw rats. A significantly greater increase was seen in SS.BN13 rats, with PRA increasing from 0.6±0.1 to 2.4±0.3 ng Ang I/mL per hour. The greatest increase was found in BN/Mcw rats, with PRA increasing from 1.5±0.2 to 7.0±0.8 ng Ang I/mL per hour.
Renal Morphology and Urine Protein and
Creatinine Excretion in High Salt–Fed Rats
Protein excretion of SS.BN13 rats on the 4% salt diet
(63±18 mg/24 h) was significantly less than that of the SS/Mcw rats
(190±30 mg/24 h). BN/Mcw rats averaged 40±6 mg/24 h, a level not
significantly different from that seen in SS.BN13 rats. Plasma
creatinine concentration was nearly identical in the 3
strains (0.4±0.04 mg/dL), and creatinine clearances did
not differ significantly, averaging 1.8±0.3, 1.4±0.2, and 1.2±0.2
mL/min in SS/Mcw, SS.BN13, and BN/Mcw rats, respectively.
Glomerular injury and tubular interstitial disease as assessed morphologically are illustrated in Figure 2. SS/Mcw rats exhibited considerable tubular interstitial disease, averaging 23.8±2% PAS positive in the outer medulla of rats fed a high salt diet, in accord with data we have previously reported.22 Tubular fibrosis was seen in the thick ascending limbs of Henle (protein casts), leading to fibrotic elimination of the vasa recta in the SS/Mcw rats. In contrast, this region of the kidney in consomic SS.BN13 rats appeared to be well protected from the damage of the high salt diet (Figure 2), averaging significantly less PAS-positive damage (7.9±2%) than that found in the SS/Mcw rats. BN/Mcw rats averaged 14.7±2% PAS-positive damage, a value significantly less than that found in SS/Mcw rats but greater (P<0.05) than that in SS.BN13 rats.
|
There was marked expansion of the mesangial matrix in the glomeruli and loss of capillaries in the SS/Mcw rat, yielding a mean glomerular injury index of 2.2±0.1. This was similar to that measured in SS.BN13 rats (2.1±0.5). Both were significantly greater than that seen in the BN/Mcw rats, which averaged 1.1±0.2. These observations indicate that the SS.BN13 rats were protected from the salt-induced medullary interstitial nephritis but not from glomerular disease.
Responsiveness to Ang II and NE
The average MAP of SS/Mcw rats on a high (4%) salt
diet remained higher even under anesthesia (124±4
mm Hg) compared with that of the BN/Mcw rats (111±3 mm Hg) and
the consomic SS.BN13 rats (114±3 mm Hg). The
arterial pressure Ang II and NE dose-response relationships
did not significantly differ in these 3 strains of rats (data not
shown). In contrast, major differences were observed in the renal
vascular responses to these compounds, with SS/Mcw rats exhibiting
significantly greater increases of renal vascular resistance in
response to both Ang II and NE infusions than those found in the BN/Mcw
or SS.BN13 rats
(Figure 3).
|
, n=16), SS.BN13 (
, n=13), and BN/Mcw (• , n=14) rats. Bottom, Renal vascular resistance dose-response relationship to 3 doses of NE in SS/Mcw (
GFR and Filtration Fractions in Rats Maintained
on a 0.4% Salt Diet
As summarized in the
Table,
GFR values, normalized per gram kidney weight, and filtration fractions
of SS.BN13 rats were significantly higher than those of SS/Mcw rats and
did not differ from those of BN/Mcw rats. RBF values of SS/Mcw and
SS.BN13 rats were significantly different from each other and from
those of BN/Mcw rats. The average left kidney weights of SS/Mcw and
SS.BN13 rats did not differ from each other, and both were
significantly greater than those of BN/Mcw rats. The fractional
excretion of Na+ did not differ
significantly among the 3 strains of rats; however, fractional
excretion of K+ was significantly higher in
SS/Mcw rats than in SS.BN13 rats.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Influence of Chromosome 13 on Blood Pressure
The results demonstrate that substitution of BN/Mcw chromosome 13 on the isogenic background of the inbred SS/Mcw rat nearly abolished the rise of arterial pressure and associated proteinuria observed with a high salt diet in the parental SS/Mcw rats. These data suggest that a gene, or set of genes, on BN/Mcw chromosome 13 confers protection from salt-induced hypertension in the SS/Mcw rat. These studies provide a strong rationale to begin narrowing and searching for candidate genes of hypertension and/or renal disease on chromosome 13.
Influence of Chromosome 13 on Renal
Function
Kidney morphology of the consomic SS.BN13 rats after 4
weeks of a high salt diet was not entirely normal compared with that of
the BN/Mcw rats, inasmuch as the consomic rats did not appear to be
protected from the development of glomerular sclerosis.
However, despite the similar glomerular injury scores seen
in the SS/Mcw and SS.BN13 rats, SS.BN13 rats did not exhibit the severe
proteinuria seen in SS/Mcw rats. It appears that the semiquantitative
glomerular injury index does not reflect functional
differences in glomeruli that could importantly influence
glomerular protein sieving and/or proximal tubular
reabsorption of filtered proteins. Preliminary morphological studies in
our laboratory (J.G.D.) indicate that the glomerular
sclerosis seen in SS.BN13 rats was a result of the high salt diet,
because when maintained on a low salt diet (0.4%), they exhibit no
apparent injury.
The outer medulla of the consomic SS.BN13 rats had normal fibrotic deposition, a remarkable observation because it was this region of the SS/Mcw kidneys that exhibited severe fibrosis of capillaries and tubular interstitial disease after 2 to 4 weeks of the high salt feeding seen in a previous study.22 It remains to be determined whether the renal protective effects, conferred to SS/Mcw rats by BN/Mcw chromosome 13, were secondary to the antihypertensive effect of chromosomal transfer or a direct protective effect.
Chromosome 13 and the SS/Mcw Rat
Blood pressure responsiveness to Ang II and NE among
the 3 strains of rats did not differ, as assessed by the pressure
dose-response relationships. In contrast, SS/Mcw rats exhibited
substantially greater increases of renal vascular resistance in
response to both of these compounds than did the SS.BN13 rats and
BN/Mcw rats. These results suggest that chromosome 13 of the BN/Mcw
rats contains genes that influence the pathways involved in buffering
of renal vasoconstrictor responses or autoregulatory
responsiveness.
Rat chromosome 13 has been the object of a number of studies because it contains the renin gene, and there is evidence that a polymorphism in the renin gene cosegregates with blood pressure in an F2 population derived from a cross of SS/Jr and SR/Jr rats.23 The results obtained from congenic strain studies suggest that both prohypertensive and antihypertensive genes exist on chromosome 13. For example, transfer of a small 10-cM segment from the Dahl R to SS rats of a region of chromosome 13 flanking the renin locus resulted in an increase of renin activity and greater elevations of blood pressure with salt feeding than were seen in the parental SS rats.17 Consistent with this view, St Lezin et al24 found that transfer of this region from SS rats reduced PRA and blood pressure in Dahl R rats. On the other hand, DiPaolo et al25 found that transfer of a larger region from Dahl R rats lowered blood pressure by 25 mm Hg and had no effect on PRA in congenic SS rats. More recently, Zhang et al26 localized this antihypertensive gene to the interval between Syt 2 and D13 Mit108, which excluded the renin gene. In the present study, transferring the entire chromosome 13 from the BN/Mcw into the Dahl S genetic background increased PRA. Despite the increased PRA, the net effect of the genes on BN/Mcw chromosome 13 was to prevent salt-induced hypertension. Thus, a powerful antihypertensive gene(s) must lie on chromosome 13 that can overcome the prohypertensive effect of transferring a normal renin gene and elevating PRA in SS/Mcw rats.
Power of Chromosomal Substitution
Studies
The results of the present study demonstrate the
power of the consomic design for mapping important functional traits
and the ability of these chromosomal substitution studies to guide us
toward genomic regions important in hypertension and other complex
traits. The present results were unexpected because our genetic
linkage study between the SS/Mcw and BN/Mcw
rats14 15 failed to
reveal significant blood pressure QTLs on chromosome 13, although
chromosome 13 has been implicated in several other studies using F2
crosses23 and congenic rat
studies24 25 26
as described above. On the basis of statistical modeling of data (not
presented in the present article), it appears that the
heterogeneous genetic background of the F2 masked the
effects of the powerful antihypertensive alleles contained on
chromosome 13. The power of the consomic approach is that it enables
one to avoid the confounding effects of heterogeneous
genomic backgrounds in which the phenotypic noise may make the
detection of weak or complex QTLs difficult. These observations support
the conclusions of others that chromosome-substitution approaches
provide greater statistical power to detect linkage than do standard
intercross linkage
studies.19 27
Consomic rats also provide a renewable source of animals for subsequent
genetic, physiological, and/or longitudinal
studies, which would narrow and examine a QTL on the chromosome by
facilitating the development of congenic substrains on an identical
genomic
background.
|
Acknowledgments |
|---|
This work was supported by grants HL-54998, HL-29587, U10 HL-154508, and U10 HL-66579 and a grant from the Merck Genome Research Institute. The authors wish to thank Kate Senkbeil, Sheri Jene, Paulo Soares, Annette Dahly, and Terry Kurth for their excellent technical assistance in the animal studies, Camille Torres and Luanne Kelly for the analytical measurements, and Christine Kendziorski for statistical modeling.
Received October 26, 2000; first decision November 30, 2000; accepted December 13, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Cowley AW Jr, Roman RJ. The role of the kidney in hypertension. JAMA. 1996;275:1581–1589.
2.
Campese VM. Salt
sensitivity in hypertension.
Hypertension. 1994;23:531–550.
3.
Grim CE, Wilson TW,
Nicholson GD, Hassell TA, Fraser HS, Grim CM, Wilson DM. Blood pressure
in blacks. Hypertension. 1990;15:803–809.
4.
Rapp JP, McPartland
RP, Sustarsic DL. Anomalous response of urinary kallikrein to
deoxycorticosterone in Dahl salt-sensitive rats.
Hypertension. 1982;4:20–26.
5.
Buchanan TA, Sipes
GF, Gadalah S, Yip KP, Marsh DJ, Hseuh W, Bergman RN. Glucose tolerance
and insulin action in rats with renovascular hypertension.
Hypertension. 1991;18:341–347.
6.
Reaven GM, Twersky
J, Chung H. Abnormalities of carbohydrate and lipid metabolites in Dahl
rats. Hypertension. 1991;18:630–635.
7. Sharma JN, Fernandez PG, Kim BK, Triggle CR. Systolic blood pressure responses to enalapril maleate and hydrochlorothiazide in conscious Dahl salt-sensitive rats. Can J Physiol Pharmacol. 1984;62:846–849.[Medline] [Order article via Infotrieve]
8. Von Lutterotti N, Camargo MJ, Mueller FB, Timmermans PB, Laragh JH. Angiotensin II receptor antagonist markedly reduces mortality in salt-loaded Dahl S rats. Am J Hypertens. 1991;4:346S–349S.[Medline] [Order article via Infotrieve]
9.
Tobian L, Lange J,
Iwai J, Hiller K, Johnson MA, Goossens P. Prevention with thiazide of
NaCl-induced hypertension in Dahl S rats.
Hypertension. 1979;1:316–323.
10. Rostand GS, Kirk KA, Rutsky EA, Pate BA. Racial differences in the incidence of treatment for end-stage renal disease. N Engl J Med. 1982;306:1276–1279.[Medline] [Order article via Infotrieve]
11. Hamet P, Pausova Z, Adarichev V, Adarichev K, Temblay J. Hypertension: genes and environment. J Hypertens. 1998;16:397–418.[Medline] [Order article via Infotrieve]
12. Zicha J, Kunes J. Ontogenetic aspects of hypertension development: analysis in the rat. Physiol Rev.1999;79:1227–1282.
13.
Rapp JP. Genetic
analysis of inherited hypertension in the rat.
Physiol Rev. 2000;80:135–172.
14.
Cowley AW Jr,
Stoll M, Greene AS, Kaldunski ML, Roman RJ, Tonellato PJ, Schork NJ,
Dumas P, Jacob HJ. Genetically defined risk of salt sensitivity in
an intercross of Brown Norway and Dahl S rats.
Physiol Genomics. 2000;2:107–115.
15. Stoll M, Cowley AW Jr, Greene AS, Kaldunski ML, Roman RJ, Tonellato PJ, Wang Z, Jacob HJ. Dissecting the genetics of hypertension using likely determinant phenotypes and pharmacogenetics. J Hypertens. 2000;8(suppl 4):S170. Abstract.
16. Rapp JP, Garrett MR, Dene H, Meng H, Hoebee B, Lathrop GM. Linkage analysis and construction of a congenic strain for a blood pressure QTL on rat chromosome 9. Genomics. 1998;51:191–196.[Medline] [Order article via Infotrieve]
17.
Jiang J, Stec DE,
Drummond H, Simon JS, Koike G, Jacob HJ, Roman RJ. Transfer of a
salt-resistant renin allele raises blood pressure in Dahl
salt-sensitive rats.
Hypertension. 1997;29:619–627.
18. Markel P, Shu P, Ebeling C, Carlson GA, Nagle D, Smutko JS, Moore KJ. Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nat Genet. 1997;15:280–284.
19. Nadeau JH, Singer A, Matin A, Lander ES. Analyzing complex genetic traits with chromosome strains. Nat Genet. 2000;24:221–225.[Medline] [Order article via Infotrieve]
20.
Ledderhoss C,
Mattson DL, Skelton MM, Cowley AW Jr. In vivo diuretic actions
of renal vasopressin V1 receptor stimulation in rats.
Am J Physiol. 1995;268:R796–R807.
21. Raij L, Azar S, Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int. 1984;26:137–143.[Medline] [Order article via Infotrieve]
22. Johnson R, Gordon KL, Ziachelli C, Kurth T, Skelton MM, Cowley AW Jr. Tubulointerstitial injury and loss of nitric oxide synthases parallel the development of hypertension in Dahl SS rats. J Hypertens. 2000;18:1–9.
23.
Rapp JP, Wang S-M,
Dene H. A genetic polymorphism in the renin gene of Dahl rats
cosegregates with blood pressure.
Science. 1989;243:542–544.
24. St Lezin EM, Pravenec M, Wong AL, Liu W, Wang N, Lu S, Jacob HJ, Roman RJ, Stec DE, Wang JM, et al. Effects of renin gene transfer on blood pressure and renin gene expression in a congenic strain of Dahl salt-sensitive rats. J Clin Invest. 1996;15:522–527.
25. DiPaola NR, Rapp JP, Brand PH, Beierwaltes WH, Metting PJ, Britton SL. Evaluation of the renin-angiotensin system in a congenic renin Dahl salt-sensitive rat. Genes Funct. 1997;1:215–226.[Medline] [Order article via Infotrieve]
26. Zhang QY, Dene H, Deng AY, Garrett MR, Jacob HS, Rapp JP. Interval mapping and congenic strains for a blood pressure QTL on rat chromosome 13. Mamm Genome. 1997;8:636–641.[Medline] [Order article via Infotrieve]
27. Matin A, Collin GB, Asada Y, Varnum D, Nadeau JH. Susceptibility to testicular germ-cell tumors in a 129.MOLF-Chr 19 chromosome substitution strain. Nat Genet. 1999;23:237–240.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. S. Amin, E. Reza, H. Wang, and F. H.H. Leenen Sodium Transport in the Choroid Plexus and Salt-Sensitive Hypertension Hypertension, October 1, 2009; 54(4): 860 - 867. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Stadnicka, S. J. Contney, C. Moreno, D. Weihrauch, Z. J. Bosnjak, R. J. Roman, and T. A. Stekiel Mechanism of Differential Cardiovascular Response to Propofol in Dahl Salt-Sensitive, Brown Norway, and Chromosome 13-Substituted Consomic Rat Strains: Role of Large Conductance Ca2+ and Voltage-Activated Potassium Channels J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 727 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Tian, Y. Liu, K. Usa, D. Mladinov, Y. Fang, X. Ding, A. S. Greene, A. W. Cowley Jr, and M. Liang Novel Role of Fumarate Metabolism in Dahl-Salt Sensitive Hypertension Hypertension, August 1, 2009; 54(2): 255 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. O'Connor, L. Lu, M. Liang, and A. W. Cowley Jr A Novel Amiloride-Sensitive H+ Transport Pathway Mediates Enhanced Superoxide Production in Thick Ascending Limb of Salt-Sensitive Rats, Not Na+/H+ Exchange Hypertension, August 1, 2009; 54(2): 248 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu, R. J. Singh, K. Usa, B. C. Netzel, and M. Liang Renal medullary 11{beta}-hydroxysteroid dehydrogenase type 1 in Dahl salt-sensitive hypertension Physiol Genomics, December 12, 2008; 36(1): 52 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. de Resende, S. L. Amaral, C. Moreno, and A. S. Greene Congenic strains reveal the effect of the renin gene on skeletal muscle angiogenesis induced by electrical stimulation Physiol Genomics, October 8, 2008; 33(1): 33 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. O'Connor, L. Lu, C. Schreck, and A. W. Cowley Jr. Enhanced amiloride-sensitive superoxide production in renal medullary thick ascending limb of Dahl salt-sensitive rats Am J Physiol Renal Physiol, September 1, 2008; 295(3): F726 - F733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Mattson, M. R. Dwinell, A. S. Greene, A. E. Kwitek, R. J. Roman, H. J. Jacob, and A. W. Cowley Jr. Chromosome substitution reveals the genetic basis of Dahl salt-sensitive hypertension and renal disease Am J Physiol Renal Physiol, September 1, 2008; 295(3): F837 - F842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Mori, A. Polichnowski, P. Glocka, M. Kaldunski, Y. Ohsaki, M. Liang, and A. W. Cowley Jr. High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension J. Am. Soc. Nephrol., August 1, 2008; 19(8): 1472 - 1482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Kunert, M. R. Dwinell, I. Drenjancevic Peric, and J. H. Lombard Sex-specific differences in chromosome-dependent regulation of vascular reactivity in female consomic rat strains from a SS x BN cross Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2008; 295(2): R516 - R527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Liang, N. H. Lee, H. Wang, A. S. Greene, A. E. Kwitek, M. L. Kaldunski, T. V. Luu, B. C. Frank, S. Bugenhagen, H. J. Jacob, et al. Molecular networks in Dahl salt-sensitive hypertension based on transcriptome analysis of a panel of consomic rats Physiol Genomics, June 1, 2008; 34(1): 54 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Tian, A. S. Greene, K. Usa, I. R. Matus, J. Bauwens, J. L. Pietrusz, A. W. Cowley Jr, and M. Liang Renal Regional Proteomes in Young Dahl Salt-Sensitive Rats Hypertension, April 1, 2008; 51(4): 899 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Mattson, M. R. Dwinell, A. S. Greene, A. E. Kwitek, R. J. Roman, A. W. Cowley Jr., and H. J. Jacob Chromosomal mapping of the genetic basis of hypertension and renal disease in FHH rats Am J Physiol Renal Physiol, December 1, 2007; 293(6): F1905 - F1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Moreno, M. L. Kaldunski, T. Wang, R. J. Roman, A. S. Greene, J. Lazar, H. J. Jacob, and A. W. Cowley Jr. Multiple blood pressure loci on rat chromosome 13 attenuate development of hypertension in the Dahl S hypertensive rat Physiol Genomics, October 19, 2007; 31(2): 228 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Y. Deng Genetic basis of polygenic hypertension Hum. Mol. Genet., October 15, 2007; 16(R2): R195 - R202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Mori, P. M. O'Connor, M. Abe, and A. W. Cowley Jr Enhanced Superoxide Production in Renal Outer Medulla of Dahl Salt-Sensitive Rats Reduces Nitric Oxide Tubular-Vascular Cross-Talk Hypertension, June 1, 2007; 49(6): 1336 - 1341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Y. Deng Positional Cloning of Quantitative Trait Loci for Blood Pressure: How Close Are We?: A Critical Perspective Hypertension, April 1, 2007; 49(4): 740 - 747. [Full Text] [PDF]
|
|
|
|
|
|
N. E. Taylor, K. G. Maier, R. J. Roman, and A. W. Cowley Jr NO Synthase Uncoupling in the Kidney of Dahl S Rats: Role of Dihydrobiopterin Hypertension, December 1, 2006; 48(6): 1066 - 1071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Kunert, I. Drenjancevic-Peric, M. R. Dwinell, J. H. Lombard, A. W. Cowley Jr., A. S. Greene, A. E. Kwitek, and H. J. Jacob Consomic strategies to localize genomic regions related to vascular reactivity in the Dahl salt-sensitive rat Physiol Genomics, September 14, 2006; 26(3): 218 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Li, L. Chen, R. W. Muh, and P.-L. Li Hyperhomocysteinemia Associated With Decreased Renal Transsulfuration Activity in Dahl S Rats Hypertension, June 1, 2006; 47(6): 1094 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Lopez, R. P. Ryan, C. Moreno, A. Sarkis, J. Lazar, A. P. Provoost, H. J. Jacob, and R. J. Roman Identification of a QTL on chromosome 1 for impaired autoregulation of RBF in fawn-hooded hypertensive rats Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1213 - F1221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Taylor, P. Glocka, M. Liang, and A. W. Cowley Jr NADPH Oxidase in the Renal Medulla Causes Oxidative Stress and Contributes to Salt-Sensitive Hypertension in Dahl S Rats Hypertension, April 1, 2006; 47(4): 692 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Taylor and A. W. Cowley Jr. Effect of renal medullary H2O2 on salt-induced hypertension and renal injury Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1573 - R1579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-Z. Ying and P. W. Sanders Enhanced expression of EGF receptor in a model of salt-sensitive hypertension Am J Physiol Renal Physiol, August 1, 2005; 289(2): F314 - F321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Drenjancevic-Peric, S. A. Phillips, J. R. Falck, and J. H. Lombard Restoration of normal vascular relaxation mechanisms in cerebral arteries by chromosomal substitution in consomic SS.13BN rats Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H188 - H195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Dwinell, H. V. Forster, J. Petersen, A. Rider, M. P. Kunert, A. W. Cowley Jr., and H. J. Jacob Genetic determinants on rat chromosome 6 modulate variation in the hypercapnic ventilatory response using consomic strains J Appl Physiol, May 1, 2005; 98(5): 1630 - 1638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Mattson, M. P. Kunert, R. J. Roman, H. J. Jacob, and A. W. Cowley Jr. Substitution of chromosome 1 ameliorates L-NAME hypertension and renal disease in the fawn-hooded hypertensive rat Am J Physiol Renal Physiol, May 1, 2005; 288(5): F1015 - F1022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Mattson, C. J. Meister, and M. L. Marcelle Dietary Protein Source Determines the Degree of Hypertension and Renal Disease in the Dahl Salt-Sensitive Rat Hypertension, April 1, 2005; 45(4): 736 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Drenjancevic-Peric and J. H. Lombard Reduced Angiotensin II and Oxidative Stress Contribute to Impaired Vasodilation in Dahl Salt-Sensitive Rats on Low-Salt Diet Hypertension, April 1, 2005; 45(4): 687 - 691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Singer, A. E. Hill, J. H. Nadeau, and E. S. Lander Mapping Quantitative Trait Loci for Anxiety in Chromosome Substitution Strains of Mice Genetics, February 1, 2005; 169(2): 855 - 862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-X. Wang and P. W. Sanders Mechanism of hypertensive nephropathy in the Dahl/Rapp rat: a primary disorder of vascular smooth muscle Am J Physiol Renal Physiol, January 1, 2005; 288(1): F236 - F242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Korstanje and K. DiPetrillo Unraveling the genetics of chronic kidney disease using animal models Am J Physiol Renal Physiol, September 1, 2004; 287(3): F347 - F352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Drenjancevic-Peric and J. H. Lombard Introgression of chromosome 13 in Dahl salt-sensitive genetic background restores cerebral vascular relaxation Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H957 - H962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Singer, A. E. Hill, L. C. Burrage, K. R. Olszens, J. Song, M. Justice, W. E. O'Brien, D. V. Conti, J. S. Witte, E. S. Lander, et al. Genetic Dissection of Complex Traits with Chromosome Substitution Strains of Mice Science, April 16, 2004; 304(5669): 445 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Hoagland, A. K. Flasch, A. J. Dahly-Vernon, E. A. dos Santos, M. A. Knepper, and R. J. Roman Elevated BSC-1 and ROMK Expression in Dahl Salt-Sensitive Rat Kidneys Hypertension, April 1, 2004; 43(4): 860 - 865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Mori and A. W. Cowley Jr. Role of Pressure in Angiotensin II-Induced Renal Injury: Chronic Servo-Control of Renal Perfusion Pressure in Rats Hypertension, April 1, 2004; 43(4): 752 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Mori and A. W. Cowley Jr. Renal Oxidative Stress in Medullary Thick Ascending Limbs Produced by Elevated NaCl and Glucose Hypertension, February 1, 2004; 43(2): 341 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Mattson, M. P. Kunert, M. L. Kaldunski, A. S. Greene, R. J. Roman, H. J. Jacob, and A. W. Cowley Jr Influence of diet and genetics on hypertension and renal disease in Dahl salt-sensitive rats Physiol Genomics, January 15, 2004; 16(2): 194 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Liang, A. W. Cowley Jr, and A. S. Greene High throughput gene expression profiling: a molecular approach to integrative physiology J. Physiol., January 1, 2004; 554(1): 22 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Cowley Jr, R. J. Roman, and H. J. Jacob Application of chromosomal substitution techniques in gene-function discovery J. Physiol., January 1, 2004; 554(1): 46 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. McBride, F. J. Charchar, D. Graham, W. H. Miller, P. Strahorn, F. J. Carr, and A. F. Dominiczak Functional genomics in rodent models of hypertension J. Physiol., January 1, 2004; 554(1): 56 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Moreno, P. Dumas, M. L. Kaldunski, P. J. Tonellato, A. S. Greene, R. J. Roman, Q. Cheng, Z. Wang, H. J. Jacob, and A. W. Cowley Jr Genomic map of cardiovascular phenotypes of hypertension in female Dahl S rats Physiol Genomics, November 11, 2003; 15(3): 243 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Amaral, K. G. Maier, D. N. Schippers, R. J. Roman, and A. S. Greene CYP4A metabolites of arachidonic acid and VEGF are mediators of skeletal muscle angiogenesis Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1528 - H1535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Drenjancevic-Peric, J. C. Frisbee, and J. H. Lombard Skeletal Muscle Arteriolar Reactivity in SS.BN13 Consomic Rats and Dahl Salt-Sensitive Rats Hypertension, May 1, 2003; 41(5): 1012 - 1015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Cowley Jr. Genomics and homeostasis Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R611 - R627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Hoagland, K. G. Maier, and R. J. Roman Contributions of 20-HETE to the Antihypertensive Effects of Tempol in Dahl Salt-Sensitive Rats Hypertension, March 1, 2003; 41(3): 697 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Youngren, J. H. Nadeau, and A. Matin Testicular cancer susceptibility in the 129.MOLF-Chr19 mouse strain: additive effects, gene interactions and epigenetic modifications Hum. Mol. Genet., February 15, 2003; 12(4): 389 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Liang, B. Yuan, E. Rute, A. S. Greene, M. Olivier, and A. W. Cowley Jr. Insights into Dahl salt-sensitive hypertension revealed by temporal patterns of renal medullary gene expression Physiol Genomics, February 6, 2003; 12(3): 229 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Kotchen, U. Broeckel, C. E. Grim, P. Hamet, H. Jacob, M. L. Kaldunski, J. M. Kotchen, N. J. Schork, P. J. Tonellato, and A. W. Cowley Jr Identification of Hypertension-Related QTLs in African American Sib Pairs Hypertension, November 1, 2002; 40(5): 634 - 639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.J. ROMAN, A.W. COWLEY, A. GREENE, A.E. KWITEK, P.J. TONELLATO, and H.J. JACOB Consomic Rats for the Identification of Genes and Pathways Underlying Cardiovascular Disease Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 309 - 316. [Abstract] [PDF]
|
|
|
|
 |
|
 O. Grisk and R. Rettig Renal Transplantation Studies in Genetic Hypertension Physiology, December 1, 2001; 16(6): 262 - 265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Liang, B. Yuan, E. Rute, A. S. Greene, A.-P. Zou, P. Soares, G. D. MCQuestion, G. R. Slocum, H. J. Jacob, and A. W. Cowley Jr. Renal medullary genes in salt-sensitive hypertension: a chromosomal substitution and cDNA microarray study Physiol Genomics, February 28, 2002; 8(2): 139 - 149. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||