Consomic strategies to localize genomic regions related to vascular reactivity in the Dahl salt-sensitive rat

2006 ◽  
Vol 26 (3) ◽  
pp. 218-225 ◽  
Author(s):  
Mary Pat Kunert ◽  
Ines Drenjancevic-Peric ◽  
Melinda R. Dwinell ◽  
Julian H. Lombard ◽  
Allen W. Cowley ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Aortic Ring ◽  
Gene Interaction ◽  
Brown Norway ◽  
Single Chromosome ◽  
Salt Diet ◽  
Vasoactive Substances ◽  
Consomic Strain ◽  
Genomic Regions ◽  
Or Genes

Chromosomal substitution strains afford the opportunity to discover regions of the rat genome that contain genes related to cardiovascular traits with the long-range goal of linking these genes to physiological function. PhysGen (Programs for Genomic Applications) created a consomic panel of rats derived from the introgression of a single chromosome (≥95% of the BN chromosome, one at a time) of the Brown Norway (BN/NHsdMcwi) rat onto the homogeneous genetic background of the Dahl salt-sensitive rat (SS/JrHsdMcwi). For 3 wk before the experiment, the rats were maintained on a low-salt diet (0.4% NaCl). The dose response of aortic rings from each strain of rat to phenylephrine, acetylcholine, sodium nitroprusside, and three different levels of tissue bath hypoxia (10, 5, and 0% O2) was measured and compared with the parental SS rat. To maximize the possibility that differences among the strains would become apparent, each strain of rat including the parental SS and BN was also studied after being maintained on a high-salt diet (4.0% NaCl) for 3 wk. If the response of the aortic ring from a consomic strain to these vasoactive substances was different from that of the SS parental strain, it was concluded that the introgressed chromosome contained a gene or genes that contributed to that difference. Because the BN chromosome is removed from its native background and the SS rat loses a native chromosome, it is also necessary to consider the contribution of changes in gene-to-gene interaction.

scholarly journals Sex-specific differences in chromosome-dependent regulation of vascular reactivity in female consomic rat strains from a SS × BN cross

2008 ◽  
Vol 295 (2) ◽  
pp. R516-R527 ◽  
Author(s):  
Mary Pat Kunert ◽  
Melinda R. Dwinell ◽  
Ines Drenjancevic Peric ◽  
Julian H. Lombard
Keyword(s):  
Vascular Reactivity ◽  
Aortic Ring ◽  
Environmental Variable ◽  
Brown Norway ◽  
High Salt Diet ◽  
Salt Diet ◽  
Medical College ◽  
Expression Of Genes ◽  
Consomic Strain ◽  
Induced Changes

High-throughput studies in the Medical College of Wisconsin Program for Genomic Applications (Physgen) were designed to link chromosomes with physiological function in consomic strains derived from a cross between Dahl salt-sensitive SS/JrHsdMcwi (SS) and Brown Norway normotensive BN/NHsdMcwi (BN) rats. The specific goal of the vascular protocol was to characterize the responses of aortic rings from these strains to vasoconstrictor and vasodilator stimuli (phenylephrine, acetylcholine, sodium nitroprusside, and bath hypoxia) to identify chromosomes that either increase or decrease vascular reactivity to these vasoactive stimuli. Because previous studies demonstrated sex-specific quantitative trait loci (QTLs) related to regulation of cardiovascular phenotypes in an F2 cross between the parental strains, males and females of each consomic strain were included in all experiments. As there were significant sex-specific differences in aortic sensitivity to vasoconstrictor and vasodilator stimuli compared with the parental SS strain, we report the results of the females separately from the males. There were also sex-specific differences in aortic ring sensitivity to these vasoactive stimuli in consomic strains that were fed a high-salt diet (4% NaCl) for 3 wk to evaluate salt-induced changes in vascular reactivity. Differences in genetic architecture could contribute to sex-specific differences in the development and expression of cardiovascular diseases via differential regulation and expression of genes. Our findings are the first to link physiological traits with specific chromosomes in female SS rats and support the idea that sex is an important environmental variable that plays a role in the expression and regulation of genes.

scholarly journals Vascular responses in aortic rings of a consomic rat panel derived from the Fawn Hooded Hypertensive strain

2010 ◽  
Vol 42A (4) ◽  
pp. 244-258 ◽  
Author(s):  
Mary Pat Kunert ◽  
Melinda R. Dwinell ◽  
Julian H. Lombard
Keyword(s):  
Genetic Background ◽  
Vascular Reactivity ◽  
Salt Intake ◽  
Aortic Ring ◽  
Brown Norway ◽  
Dietary Salt ◽  
Dietary Salt Intake ◽  
Low Salt ◽  
Insight Into

The present experiments, utilizing the high-throughput vascular protocol of PhysGen (Program for Genomic Applications) characterized the responses of aortic rings to vasoconstrictor (phenylephrine) and vasodilator (acetylcholine, sodium nitroprusside, and reduced tissue bath Po2) stimuli in consomic rat strains derived from a cross between the Fawn Hooded Hypertensive rat (FHH/EurMcwi) and the Brown Norway normotensive (BN/NHsdMcwi) rat. The effects of substituting individual BN chromosomes into the FHH genetic background were determined in animals that were maintained on a low-salt (0.4% NaCl) diet or switched to a high-salt (4% NaCl) diet for 3 wk. Sex-specific differences were evaluated in male and female consomic rats on similar dietary salt intake. Multiple chromosomes affected various vascular reactivity phenotypes in the FHH × BN consomic panel, and substantial salt-dependent changes in vascular reactivity and sex-specific differences in aortic reactivity were observed in individual consomic strains. However, compared with earlier studies of consomic rats derived from a cross between the BN rat and the Dahl salt-sensitive (SS) rat, only 3–7% of the vascular phenotypes were affected in a similar manner by substituting specific BN chromosomeschromosomes into the FHH genetic background versus the SS genetic background. The findings of the present study stress the potential value of consomic rat panels in gaining insight into genetic factors influencing vascular reactivity and suggest that the chromosomes that appear to be involved in the determination of aortic ring reactivity in different rodent models of hypertension are highly strain- and sex specific.

scholarly journals Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries

2017 ◽  
Vol 312 (6) ◽  
pp. F971-F981 ◽  
Author(s):  
Fan Fan ◽  
Mallikarjuna R. Pabbidi ◽  
Ying Ge ◽  
Longyang Li ◽  
Shaoxun Wang ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Cerebral Arteries ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Myogenic Response ◽  
Norway Rat ◽  
Vasoconstrictor Response ◽  
Brown Norway Rat ◽  
Interfering Rna

We have reported that the myogenic response of the renal afferent arteriole (Af-art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow are impaired in Fawn-Hooded Hypertensive (FHH) rats. Transfer of a region of chromosome 1 containing γ-adducin (Add3) from the Brown Norway rat rescued the vascular dysfunction and the development of renal disease. To examine whether Add3 is a viable candidate gene altering renal and cerebral hemodynamics in FHH rats, we knocked down the expression of Add3 in rat Af-arts and MCAs cultured for 36-h using a 27-mer Dicer-substrate short interfering RNA (DsiRNA). Control Af-arts constricted by 10 ± 1% in response to an elevation in pressure from 60 to 120 mmHg but dilated by 4 ± 3% when treated with Add3 DsiRNA. Add3 DsiRNA had no effect on the vasoconstrictor response of the Af-art to norepinephrine (10−7 M). Add3 DsiRNA had a similar effect on the attenuation of the myogenic response in the MCA. Peak potassium currents were threefold higher in smooth muscle cells isolated from Af-arts or MCAs transfected with Add3 DsiRNA than in nontransfected cells isolated from the same vessels. This is the first study demonstrating that Add3 plays a role in the regulation of potassium channel function and vascular reactivity. It supports the hypothesis that sequence variants in Add3, which we previously identified in FHH rats, may play a causal role in the impaired myogenic response and autoregulation in the renal and cerebral circulation.

Abstract 36: Deficiency in the Production of 20-HETE Contributes to Impaired Myogenic and TGF Responses in the Afferent Arteriole of Dahl S Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ying Ge ◽  
Fan Fan ◽  
Sydney R Murphy ◽  
Jan Michael Williams ◽  
Ruisheng Liu ◽  
...  
Keyword(s):  
Renal Injury ◽  
Tubuloglomerular Feedback ◽  
Brown Norway ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Afferent Arteriole ◽  
Synthesis Inhibitor ◽  
Renal Vasculature ◽  
Luminal Diameter ◽  
Consomic Strain

Previous studies have indicated that a deficiency in the formation of 20-HETE in the proximal tubule and thick ascending limb of Henle in Dahl S rats increases sodium reabsorption and contributes to the development of hypertension. The present study examined whether the lack of 20-HETE production in the renal vasculature contributes to the progression of renal injury by altering the myogenic or tubuloglomerular feedback (TGF) response of the afferent arteriole (Af-Art). The production of 20-HETE was significantly lower by 54% in renal microvessels isolated from the kidneys of Dahl S rats versus that seen than in SS.5BN consomic strain in which chromosome 5 from the Brown Norway (BN) rat containing the CYP4A genes responsible for the formation of 20-HETE was transferred into the Dahl S genetic background. The luminal diameter of the Af-Art decreased by 14.7± 1.5% (from 20.5 ± 0.7 to 17.5 ± 0.8 μm, n=6) in SS.5BN rats whereas the diameter of the Af-Art remained unaltered in Dahl S rats (from 20.1 ± 0.6 to 21.7 ± 0.6 μm, n=7) when the perfusion pressure was increased from 60 mmHg to 120 mmHg. In other experiments, adenosine (1 μM) reduced the diameter of the Af-Art in the SS.5BN rats by 15±0.7% (from 20.1 ±0.4 to 17.1 ± 0.9 μm, n=3) whereas the Af-Art of Dahl S rats was unaltered. However, administration of a 20-HETE synthesis inhibitor, HET0016 (1 μM, n=6), or a selective 20-HETE antagonist, 6, 15-20-HEDE (10 μM, n=6) completely blocked the myogenic and adenosine responses in the Af-Art of SS.5BN rats but it had no effect in Dahl S rats. Administration of a 20-HETE agonist, 5, 14-20-HEDE (1 μM) restored the myogenic response (from 20.7 ± 0.7 to 17.6 ± 0.6 μm, n=7) and vasoconstrictor response to adenosine in the Af-Art of Dahl S rats. These studies confirm the key role of 20-HETE in modulating the responsiveness of the Af-Art and indicate that a deficiency in the formation of 20-HETE in renal microvessels contributes to the marked susceptibility of Dahl S rats to develop hypertension induced renal injury.

scholarly journals Physiological and Biochemical Vascular Reactivity Parameters of Angiotensin II and the Action of Biased Agonist TRV023

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Marcos André Soares Leal ◽  
Thanisia de Almeida ◽  
João Guilherme Torres ◽  
Luciene Cristina Gastalho Campos ◽  
Elisardo Corral Vasquez ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Renin Angiotensin System ◽  
Aortic Ring ◽  
Experimental Models ◽  
Organ Bath ◽  
Angiotensin System ◽  
Active Peptides ◽  
Pharmacological Studies ◽  
Physiological And Biochemical

Vascular reactivity experiments using isolated aortic rings have been widely used as a model for physiological and pharmacological studies since the early sixties. Here, we suggest several parameters that the researcher should pay attention to when investigating angiotensin II in their experimental models. Angiotensin II is one of the active peptides of the renin-angiotensin system and exerts its effect through the AT1 and AT2 receptors. Some studies seek to understand the effects of angiotensin II receptors at the vascular level by using vascular reactivity experiments. However, because of the large number of variations, there are only a handful of reactivity studies that seek to use this method. Thus, the objective of this study was to standardize experimental methods with angiotensin II, through vascular reactivity protocols. For this, variables such as basal tension, concentration interval, single concentration, curve concentration response, and multiple experiments using the same aortic ring were developed using the technique of vascular reactivity in an organ bath. This is the first study that has standardized the vascular reactivity protocol. In addition, we demonstrated the effects of TRV023-biased ligand of the AT1R at vascular sites.

scholarly journals Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

2012 ◽  
Vol 302 (10) ◽  
pp. R1209-R1218 ◽  
Author(s):  
Jan M. Williams ◽  
Fan Fan ◽  
Sydney Murphy ◽  
Carlos Schreck ◽  
Jozef Lazar ◽  
...  
Keyword(s):  
Genetic Background ◽  
Chronic Administration ◽  
Brown Norway ◽  
Glomerular Injury ◽  
Chromosome 5 ◽  
Norway Rat ◽  
Protein Excretion ◽  
Elevated Expression ◽  
Brown Norway Rat ◽  
Consomic Strain

This study examined whether substitution of chromosome 5 containing the CYP4A genes from Brown Norway rat onto the Dahl S salt-sensitive (SS) genetic background upregulates the renal production of 20-HETE and attenuates the development of hypertension. The expression of CYP4A protein and the production of 20-HETE were significantly higher in the renal cortex and outer medulla of SS.5BN (chromosome 5-substituted Brown Norway rat) consomic rats fed either a low-salt (LS) or high-salt (HS) diet than that seen in SS rats. The increase in the renal production of 20-HETE in SS.5BN rats was associated with elevated expression of CYP4A2 mRNA. MAP measured by telemetry rose from 117 ± 1 to 183 ± 5 mmHg in SS rats fed a HS diet for 21 days, but only increased to 151 ± 5 mmHg in SS.5BN rats. The pressure-natriuretic and diuretic responses were twofold higher in SS.5BN rats compared with SS rats. Protein excretion rose to 354 ± 17 mg/day in SS rats fed a HS diet for 21 days compared with 205 ± 13 mg/day in the SS.5BN rats, and the degree of glomerular injury was reduced. Baseline glomerular capillary pressure (Pgc) was similar in SS.5BN rats (43 ± 1 mmHg) and Dahl S (44 ± 2 mmHg) rats. However, Pgc increased to 59 ± 3 mmHg in SS rats fed a HS diet for 7 days, while it remained unaltered in SS.5BN rats (43 ± 2 mmHg). Chronic administration of an inhibitor of the synthesis of 20-HETE (HET0016, 10 mg·kg−1·day−1 iv) reversed the antihypertensive phenotype seen in the SS.5BN rats. These findings indicate that the transfer of chromosome 5 from the BN rat onto the SS genetic background increases the renal expression of CYP4A protein and the production of 20-HETE and that 20-HETE contributes to the antihypertensive and renoprotective effects seen in the SS.5BN consomic strain.

scholarly journals A High-Salt Diet Further Impairs Age-Associated Declines in Cognitive, Behavioral, and Cardiovascular Functions in Male Fischer Brown Norway Rats

2013 ◽  
Vol 143 (9) ◽  
pp. 1406-1413 ◽  
Author(s):  
Gaurav Chugh ◽  
Mohammad Asghar ◽  
Gaurav Patki ◽  
Ritu Bohat ◽  
Faizan Jafri ◽  
...  
Keyword(s):  
High Salt ◽  
Cognitive Behavioral ◽  
Brown Norway ◽  
High Salt Diet ◽  
Salt Diet ◽  
Norway Rats ◽  
Cardiovascular Functions

scholarly journals The Vascular Reactivity to Vasoactive Substances and the Electrolyte Contents in Arterial Walls

1965 ◽  
Vol 86 (4) ◽  
pp. 366-379 ◽  
Author(s):  
Hiroshi Demura ◽  
Soitsu Fukuchi ◽  
Hidenori Takahashi ◽  
Koji Goto
Keyword(s):  
Vascular Reactivity ◽  
Arterial Walls ◽  
Vasoactive Substances

Identification of a QTL on chromosome 1 for impaired autoregulation of RBF in fawn-hooded hypertensive rats

2006 ◽  
Vol 290 (5) ◽  
pp. F1213-F1221 ◽  
Author(s):  
Bernardo López ◽  
Robert P. Ryan ◽  
Carol Moreno ◽  
Albert Sarkis ◽  
Jozef Lazar ◽  
...  
Keyword(s):  
Genetic Background ◽  
Significant Quantitative Trait Locus ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Genetic Linkage Analysis ◽  
Hypertensive Rats ◽  
Congenic Strains ◽  
Protein Excretion ◽  
Trait Locus ◽  
Consomic Strain

The present study evaluated whether the impairment in autoregulation of renal blood flow (RBF) in the fawn-hooded Hypertensive (FHH) rat colocalizes with the Rf-1 region on chromosome 1 that has been previously linked to the development of proteinuria in this strain. Autoregulation of RBF was measured in FHH and a consomic strain (FHH.1BN) in which chromosome 1 from the Brown-Norway (BN) rat was introgressed into the FHH genetic background. The autoregulation indexes (AI) averaged 0.80 ± 0.08 in the FHH and 0.19 ± 0.05 in the FHH.1BN rats. We next performed a genetic linkage analysis for autoregulation of RBF in 85 F2 rats generated from a backcross of FHH.1BN consomic and FHH rats. The results revealed a significant quantitative trait locus (QTL) with a peak logarithm of the odds score of 6.3 near marker D1Rat376. To confirm the existence of this QTL, five overlapping congenic strains were created that spanned the region from markers D1Rat234 to D1Mit14. Transfer of a region of BN chromosome 1 from markers D1Mgh13 to D1Rat89 into the FHH genetic background improved autoregulation of RBF (AI = 0.23 ± 0.04) and reduced protein excretion. In contrast, RBF was poorly autoregulated and the rats were not protected from proteinuria in congenic strains in which other regions of chromosome 1 that exclude the D1Rat376 marker were transferred. These results indicate that there is a gene(s) that influences autoregulation of RBF and proteinuria between markers D1Mgh13 and D1Rat89 on chromosome 1 that lies within the confidence interval of the Rf-1 QTL previously linked to the development of proteinuria in FHH rats.

Molecular networks in Dahl salt-sensitive hypertension based on transcriptome analysis of a panel of consomic rats

2008 ◽  
Vol 34 (1) ◽  
pp. 54-64 ◽  
Author(s):  
Mingyu Liang ◽  
Norman H. Lee ◽  
Hongying Wang ◽  
Andrew S. Greene ◽  
Anne E. Kwitek ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Expression Patterns ◽  
Differentially Expressed ◽  
Molecular Networks ◽  
Brown Norway ◽  
Biological Knowledge ◽  
Salt Diet ◽  
Chromosome 13 ◽  
Induced Hypertension ◽  
Salt Sensitive Hypertension

The Dahl salt-sensitive (SS) rat is a widely used model of human salt-sensitive hypertension and renal injury. We studied the molecular networks that underlie the complex disease phenotypes in the SS model, using a design that involved two consomic rat strains that were protected from salt-induced hypertension and one that was not protected. Substitution of Brown Norway (BN) chromosome 13 or 18, but not 20, into the SS genome was found to significantly attenuate salt-induced hypertension and albuminuria. Gene expression profiles were examined in the kidneys of SS and consomic SS-13BN, SS-18BN, and SS-20BN rats with a total of 240 cDNA microarrays. The substituted chromosome was overrepresented in genes differentially expressed between a consomic strain and SS rats on a 0.4% salt diet. F5, Serpinc1, Slc19a2, and genes represented by three other expressed sequence tags (ESTs), which are located on chromosome 13, were found to be differentially expressed between SS-13BN and all other strains examined. Likewise, Acaa2, B4galt6, Colec12, Hsd17b4, and five other ESTs located on chromosome 18 exhibited expression patterns unique to SS-18BN. On exposure to a 4% salt diet, there were 184 ESTs in the renal cortex and 346 in the renal medulla for which SS-13BN and SS-18BN shared one expression pattern, while SS and SS-20BN shared another, mirroring the phenotypic segregation among the four strains. Molecular networks that might contribute to the development of Dahl salt-sensitive hypertension and albuminuria were constructed with an approach that merged biological knowledge-driven analysis and data-driven Bayesian probabilistic analysis.

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