Characterization of blood pressure and renal function in chromosome 5 congenic strains of Dahl S rats

Roman, Richard J.; Hoagland, Kimberly M.; López, Bernardo; Kwitek, Anne E.; Garrett, Michael R.; Rapp, John P.; Lazar, Josef; Jacob, Howard J.; Sarkis, Albert

doi:10.1152/ajprenal.00360.2005

Cited by 25 publications

(39 citation statements)

References 31 publications

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“…The S.L(5)ϫ6ϫ9 containing L alleles from 116.6 Mb to 134.9 Mb did not result in differential expression of the Cyp4a genes compared with the S rat. These data suggest that genetic factors within 116.6 to 134.9 Mb of RNO5 are not responsible for the observed changes in Cyp4a genes reported by Roman et al, 58 thus lending further support to the view that deficiency of renal formation of 20-HETE contributing to increased BP may be because of functional polymorphisms within the Cyp genes in rats 58 and in humans. 59 …”

Section: Discussionsupporting

confidence: 57%

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Cross-Talk of Expression Quantitative Trait Loci Within 2 Interacting Blood Pressure Quantitative Trait Loci

Lee

Haas²,

Letwin³

et al. 2007

Hypertension

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Abstract-Genetic dissection of the S rat genome has provided strong evidence for the presence of 2 interacting blood pressure quantitative trait loci (QTLs), termed QTL1 and QTL2, on rat chromosome 5. However, the identities of the underlying interacting genetic factors remain unknown. Further experiments targeted to identify the interacting genetic factors by the substitution mapping approach alone are difficult because of the interdependency of natural recombinations to occur at the 2 QTLs. We hypothesized that the interacting genetic factors underlying these 2 QTLs may interact at the level of gene transcription and thereby represent expression QTLs or eQTLs. To detect these interacting expression QTLs, a custom QTL chip containing the annotated genes within QTL1 and QTL2 was developed and used to conduct a transcriptional profiling study of S and 2 congenic strains that retain either 1 or both of the QTLs. The results uncovered an interaction between 2 transcription factor genes, Dmrta2 and Nfia. Furthermore, the "biological signature" elicited by these 2 transcription factors was differential between the congenic strain that retained Lewis alleles at both QTL1 and QTL2 compared with the congenic strain that retained Lewis alleles at QTL1 alone. A network of transcription factors potentially affecting blood pressure could be traced, lending support to our hypothesis.

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Section: Discussionsupporting

confidence: 57%

“…Roman et al 58 have recently provided evidence for the involvement of a genomic segment on RNO5 encompassing a family of Cyp4a genes in controlling BP of the S rat. Their data suggest that there may be additional QTLs on RNO5, which operate independent of the QTLs reported in our study.…”

Section: Discussionmentioning

confidence: 99%

Cross-Talk of Expression Quantitative Trait Loci Within 2 Interacting Blood Pressure Quantitative Trait Loci

Lee

Haas²,

Letwin³

et al. 2007

Hypertension

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“…5A). Moreover, in previous studies, we reported that blockade of the synthesis of 20-HETE has no additional effect on MAP in SS rats (28,41).…”

Section: Discussionmentioning

confidence: 72%

“…Chronic blockade of the formation of 20-HETE with HET0016 reversed the antihypertensive and renoprotective effects seen in the SS.5 BN consomic strain. In contrast, we have previously demonstrated the chronic inhibition of 20-HETE has no effect on either arterial pressure (28,41) or the degree of proteinuria and renal injury in SS rats (41). The mechanism for an increase in Pgc in SS rats fed a HS diet remains to be determined.…”

Section: Discussionmentioning

confidence: 77%

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

Williams

Fan

Murphy

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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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.5 BN (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.5 BN rats was associated with elevated expression of CYP4A2 mRNA. MAP measured by telemetry rose from 117 Ϯ 1 to 183 Ϯ 5 mmHg in SS rats fed a HS diet for 21 days, but only increased to 151 Ϯ 5 mmHg in SS.5 BN rats. The pressure-natriuretic and diuretic responses were twofold higher in SS.5 BN rats compared with SS rats. Protein excretion rose to 354 Ϯ 17 mg/day in SS rats fed a HS diet for 21 days compared with 205 Ϯ 13 mg/day in the SS.5 BN rats, and the degree of glomerular injury was reduced. Baseline glomerular capillary pressure (Pgc) was similar in SS.5 BN rats (43 Ϯ 1 mmHg) and Dahl S (44 Ϯ 2 mmHg) rats. However, Pgc increased to 59 Ϯ 3 mmHg in SS rats fed a HS diet for 7 days, while it remained unaltered in SS.5 BN rats (43 Ϯ 2 mmHg). Chronic administration of an inhibitor of the synthesis of 20-HETE (HET0016, 10 mg·kg Ϫ1 ·day Ϫ1 iv) reversed the antihypertensive phenotype seen in the SS.5 BN 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.5 BN consomic strain.hypertension; glomerulosclerosis; chromosome 5; Dahl S rats; pressure natriuresis; renal hemodynamics; kidney THE DAHL SALT-SENSITIVE (SS) rat is an inbred genetic model that rapidly develops severe hypertension, proteinuria, glomerulosclerosis, and renal interstitial fibrosis when fed a high salt (HS) diet (4, 7-8, 23, 25, 27, 30, 38, 43). However, the genes and pathways that contribute to the development of hypertension and renal disease have yet to be identified. Previous studies from our laboratory have demonstrated that the pressure natriuretic relationship is impaired in SS rats and that this is associated with increased Cl Ϫ transport in the thick ascending limb of Henle (TALH) (13, 15-16, 29, 44). They also exhibit a deficiency in the renal production of 20-HETE that contributes to the increase in loop Cl Ϫ transport (13,35,44).More recently, Mattson et al. (20) demonstrated that substitution of chromosome 5 from the Brown Norway (BN) rat onto the SS genetic background (SS.5 BN strain) attenuates the development of hypertension and proteinuria in SS.5 BN rats fed a high-salt (HS) diet for 21 days, but the mechanism is unknown. Because the CYP4A genes that produce 20-HETE are located on chromosome 5 and this region has been found to cosegre...

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“…25 Congenic Dahl-S strains harboring the entire region of chromosome 5 that contains the CYP4A genes from Lewis rats exhibit restored synthesis of outer medullary CYP4A protein and 20-HETE and have blunted blood pressure responses to salt and reduced proteinuria compared with Dahl-S strains. 11 However, experiments with different overlapping sections of the transferred chromosome raised the possibility that the CYP4A3 and A8 genes, not A1 and A2, may be responsible for the effect of retrogressing the entire region into the congenic strains. 26 In our early experiments, we measured 20-HETE in subjects with salt-sensitive hypertension in the expectation that urinary excretion might be reduced, analogous to decreased synthesis of the compound in Dahl-S kidney.…”

Section: Discussionmentioning

confidence: 99%

The T8590C Polymorphism of CYP4A11 and 20-Hydroxyeicosatetraenoic Acid in Essential Hypertension

et al. 2008

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Abstract-A role for a deficit in transport actions of 20-hydroxyeicosatetraenoic acid (20-HETE) in hypertension is supported by the following: (1) diminished renal 20-HETE in Dahl-S rats; (2) altered salt-and furosemide-induced 20-HETE responses in salt-sensitive hypertensive subjects; and (3) increased population risk for hypertension in C allele carriers of the T8590C polymorphism of CYP4A11, which encodes an enzyme with reduced catalytic activity. We determined T8590C genotypes in 32 hypertensive subjects, 25 of whom were phenotyped for salt sensitivity of blood pressure and insulin sensitivity. Urine 20-HETE was lowest in insulin-resistant, salt-sensitive subjects (Fϭ5.56; PϽ0.02). Genotypes were 13 TT, 2 CC, and 17 CT. C allele frequency was 32.8% (blacks: 38.9%; whites: 25.0%). C carriers (CCϩCT) and TT subjects were similarly distributed among salt-and insulin-sensitivity phenotypes. C carriers had higher diastolic blood pressures and aldosterone:renin and waist:hip ratios but lower furosemide-induced fractional excretions of Na and K than TT. The T8590C genotype did not relate to sodium balance or pressure natriuresis. However, C carriers, compared with TT, had diminished 20-HETE responses to salt loading after adjustment for serum insulin concentration and resetting of the negative relationship between serum insulin and urine 20-HETE to a 1-g/h lower level of 20-HETE. The effect of C was insulin independent and equipotent to 18 U/mL of insulin (⌬20-HETEϭ 2.84Ϫ0.054ϫinsulinϪ0.98ϫC; r 2 ϭ0.53; Fϭ11.1; PϽ0.001). Hence, genetic (T8590C) and environmental (insulin) factors impair 20-HETE responses to salt in human hypertension. We propose that genotype analyses with sufficient homozygous CC will establish definitive relationships among 20-HETE, salt sensitivity of blood pressure, and insulin resistance. Key Words: hypertension Ⅲ obesity Ⅲ arachidonic acid Ⅲ cytochrome P450 Ⅲ insulin Ⅲ insulin resistance T he monooxygenase derivative of arachidonic acid synthesized by CYP450 enzymes, 20-hydroxyeicosatetraenoic acid (20-HETE), is a candidate for participation in blood pressure regulation and hypertension. This could be via excess of its potent vasoconstrictor actions 1-4 or deficiency of its inhibition of tubular transport, normally exerted at the NKCC cotransporter of the thick ascending limb and at the ubiquitous renal tubular Na-K-ATPase. [5][6][7][8] Studies in Dahl-S rats 9 -11 and in angiotensin II-induced hypertension in mice 12 support the view that a diminished effect of 20-HETE on renal transport is an important mechanism in experimental hypertension. Human population studies on polymorphisms of CYP4A11 that diminish its catalytic activity to synthesize 20-HETE 13,14 are consistent with this interpretation.Our studies in essential hypertension documented abnormal 20-HETE responses to physiological 15 and pharmacological 16 natriuresis and negative relationships with serum insulin 17 but not diminished urinary excretion of 20-HETE, as expected from observations in rodents. Because Dahl-S rats are not ...

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Characterization of blood pressure and renal function in chromosome 5 congenic strains of Dahl S rats

Cited by 25 publications

References 31 publications

Cross-Talk of Expression Quantitative Trait Loci Within 2 Interacting Blood Pressure Quantitative Trait Loci

Cross-Talk of Expression Quantitative Trait Loci Within 2 Interacting Blood Pressure Quantitative Trait Loci

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

The T8590C Polymorphism of CYP4A11 and 20-Hydroxyeicosatetraenoic Acid in Essential Hypertension

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