Abstract P232: Common Variants of the Estrogen Receptor 1 Gene Predict Decreased Blood Pressure Salt-Sensitivity in Men: The GenSalt Study

Previous reports have documented increased blood pressure (BP) salt-sensitivity in women compared to men, suggesting that genes encoding sex hormones could influence BP response to sodium. In the current study, we examined the association between 799 single nucleotide polymorphisms (SNPs) in 44 genes involved in sex hormone biosynthesis, bioavailability and metabolism for their association with BP responses to sodium intervention separately in men and women. A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding-study (307.8 mmol sodium/day) was conducted among 1,906 participants from 633 Han Chinese families. Nine BP measurements were obtained at baseline and the end of each intervention period using a random-zero sphygmomanometer. Additive associations between each SNP and BP responses to low and high-sodium interventions were assessed using a mixed linear regression model to account for familial dependencies. Among men, absolute BP responses to sodium interventions decreased with the number of minor alleles of estrogen receptor 1 (ESR1) markers rs9340844, rs9397453 and rs9383951. For example, men with genotypes C/C, C/T, and T/T of rs9397453 had respective mean DBP responses [95% confidence intervals (CI)] of: -2.67 (-3.13, -2.22), -1.23 (-1.98, -0.48), and 0.08 (-2.31, 2.47) mmHg to low-sodium intervention [p=1×10 -4 ; false discovery rate (FDR)-q=0.04]; and 1.46 (1.03, 1.89), 0.19 (-0.54, 0.91), and -1.10 (-2.82, 0.61) mmHg to high-sodium intervention (p=2×10 -4 ; FDR-q=0.04). In addition, mean SBP responses (95% CI) were: -5.70 (-6.19, -5.20), -4.34 (-5.37, -3.31), and -2.65 (-5.15, -0.16) mmHg, respectively, for low-sodium intervention (p=2×10 -3 ; FDR-q=0.17); and 4.56 (4.12, 4.99), 3.47 (2.63, 4.30), and 1.97 (-0.49, 4.43) mmHg, respectively, for high-sodium intervention (p=3×10 -3 ; FDR-q=0.40). ESR1 variants were not associated with BP responses in women, with highly significant genotype-gender interactions noted. In summary, we identified strong, consistent associations between genetic variants in the ESR1 gene and decreased salt-sensitivity in men. Although replication of these findings is needed, our results support a role for sex-hormones in the etiology of this complex trait. Funding(This research has received full or partial funding support from the American Heart Association, National Center)

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Abstract P242: Role of Human Renal Proximal Tubule Sodium Bicarbonate Cotransporter NBCe2 (SLC4A5) in Salt Sensitivity of Blood Pressure

Hypertension ◽

10.1161/hyp.66.suppl_1.p242 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

John J Gildea ◽

Julia M Carlson ◽

Tran T Hanh ◽

Dora Bigler Wang ◽

Peng Xu ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Bicarbonate ◽

Sodium Transport ◽

Renal Tissue ◽

Salt Sensitivity ◽

Bicarbonate Transport ◽

Nucleotide Polymorphisms ◽

High Sodium ◽

Sodium Bicarbonate Cotransporter ◽

Renal Tubular

The sodium bicarbonate cotransporter NBCe2 (encoded by SLC4A5) partially regulates renal tubular sodium bicarbonate transport. Hypothesis: since SLC4A5 single nucleotide polymorphisms (SNPs, rs10177833 and rs7571842) are associated with salt sensitivity of blood pressure, the gene product, NBCe2, would be involved with the etiology of human salt sensitivity. NBCe2 was localized in freshly fixed renal tissue and in primary and immortalized RPT cell (RPTC) cultures from tissue or isolated from urine. Basal expression of NBCe2 mRNA and protein was not different between RPTCs carrying WT or HV SLC4A5 before or after dopaminergic or angiotensin (II and III) stimulation. However, total transcellular sodium transport, NHE3 protein expression, and Cl-/HCO3- exchanger activity were higher in SLC4A5 HV than WT RPTCs (WT: 8.6±1.2 mM NaCl n=6, 5207.1±386.4 RFU n=36, 0.265±0.006 pH unit/min, n=33 respectively; VS HV: 14.75±0.7 mM NaCl n=4, 6946.2±500.4 RFU n=48, 0.314±0.018 pH unit/min n=35 respectively, p<0.01). Aberrant sodium transport was even more evident after increasing intracellular sodium, which resulted in increased NBCe2 mRNA, NBCe2 protein and bicarbonate transport in HV RPTCs compared to WT (WT 146% ± 24% , 109% ± 4.7%, 89% ± 4.5%, respectively, VS HV 214% ± 23%, 128% ± 5.7%, 141% ± 4.8%, respectively N=8-12, p<0.05). RPTCs carrying HV variants showed increased binding of HNF4A to SLC4A5 DNA, which was blocked by two HNF4A antagonists. Assays in RPTCs isolated from urine showed increased bicarbonate-dependent pH recovery in RPTCs from salt-sensitive subjects who are HV for SLC4A5. NBCe2 under high sodium is hyper-responsive in RPTCs carrying SLC4A5 HV through an aberrant HNF4A-mediated mechanism.

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Abstract 025: Urine Angiotensinogen and Salt-Sensitivity of Blood Pressure: The GenSalt Study

Circulation ◽

10.1161/circ.127.suppl_12.a025 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Casey M Rebholz ◽

Jing Chen ◽

Qi Zhao ◽

Dongfeng Gu ◽

Jichun Chen ◽

...

Keyword(s):

Blood Pressure ◽

Standard Deviation ◽

Confidence Interval ◽

Systolic Blood Pressure ◽

Salt Sensitivity ◽

Angiotensin System ◽

High Sodium ◽

Low Sodium ◽

Study Participants ◽

Urine Levels

Urine excretion of angiotensinogen (AGT) has been proposed as a biomarker of intrarenal renin-angiotensin system activity, and therefore as a proxy for blood pressure regulation and sodium homeostasis. The association between urine levels of AGT and blood pressure response to dietary sodium intake has not been previously examined in the general population. We assessed the hypothesis that there is a direct relationship between urine levels of AGT and salt-sensitivity of blood pressure among participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) replication study. A 7-day low-sodium intervention, followed by a 7-day high-sodium intervention was carried out among 698 GenSalt-replication study participants from rural areas of north China. Absolute urine AGT excretion (μg/24 hours) and AGT-to-creatinine ratio (AGT/Cr, μg/g) were estimated at baseline for a random sample of 100 study participants. Nine blood pressure measurements were obtained at baseline and on the last three days of each intervention period. The absolute and percent changes in mean blood pressure from low-sodium to high-sodium intervention were used to assess salt-sensitivity. Median AGT and AGT/Cr were significantly (both p=0.01) reduced during the low-sodium intervention (AGT: 7.16 μg/24 hours, AGT/Cr: 8.36 μg/g) and increased during the high-sodium intervention (AGT: 8.84 μg/24 hours, AGT/Cr: 10.92 μg/g) compared to baseline (AGT: 8.28 μg/24 hours, AGT/Cr: 9.40 μg/g). Log-transformed AGT and AGT/Cr ratio at baseline was significantly and positively associated with blood pressure at baseline and at the end of each intervention. For example, one standard deviation higher log-transformed AGT/Cr ratio (1.2 μg/g) was associated with a 4.0 mm Hg (95% confidence interval: 1.3, 6.7) higher systolic blood pressure level at the end of the high-sodium intervention (p=0.004). One standard deviation higher log-transformed AGT/Cr ratio was associated with 1.58-times increased odds of high salt-sensitivity (≥5% change) of blood pressure (95% confidence interval: 1.00, 2.50; p=0.049). Log-transformed AGT/Cr ratio at baseline was positively associated with absolute and percent systolic blood pressure change from low- to high-sodium interventions (absolute: r=0.23, p=0.02; percent: r=0.20, p=0.047). In conclusion, elevated levels of urine AGT are associated with sodium-sensitivity of blood pressure. Augmentation of renal-angiotensin system activity may play an important role in the development of salt-sensitive hypertension.

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Abstract P234: Genetic Variants of the Kallikrein-kinin System Associated with the Salt Sensitivity of Blood Pressure: The GenSalt Study

Circulation ◽

10.1161/circ.125.suppl_10.ap234 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Dongfeng Gu ◽

Qi Zhao ◽

Tanika N Kelly ◽

James E Hixson ◽

Dabeeru C Rao ◽

...

Keyword(s):

Blood Pressure ◽

Genetic Variants ◽

Dietary Intervention ◽

Linkage Disequilibrium Block ◽

Salt Sensitivity ◽

Dietary Sodium ◽

Kinin System ◽

High Sodium ◽

Low Sodium ◽

Kallikrein Kinin System

The kallikrein-kinin system (KKS) has been implicated in the pathogenesis of salt-sensitive hypertension in animal models. We comprehensively examined the association between genetic variants of the KKS and blood pressure (BP) response to dietary sodium intervention among participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study. A 7-day low-sodium dietary intervention followed by a 7-day high-sodium dietary intervention was carried out among 1,906 GenSalt participants from rural areas of north China. Nine BP measurements were obtained at baseline and on the last three days of each intervention period using a random-zero sphygmomanometer. The percentage changes in mean BP from baseline to low-sodium intervention and from low-sodium to high-sodium intervention were used to assess individual salt-sensitivity. A total of 205 tagSNPs and functional SNPs of eleven genes of the KKS ( BDKRB1 , BDKRB2 , CPN1 , CPN2 , CPM , ECE1 , KLK1 , KLKB1 , KNG1 , MME , SERPINA4 ) were selected and genotyped in this study. Single marker analyses were conducted using the Family Based Association Test program. Genetic variants in the bradykinin receptor B2 ( BDKRB2 ) and endothelin converting enzyme 1 ( ECE1 ) genes showed significant associations with salt sensitivity even after adjusting for multiple testing using the false discovery rate method. SNP rs11847625 of BDKRB2 was significantly associated with systolic BP (SBP) response to low-sodium intervention ( P = 0.0001). Compared to its major allele G, carriers of the minor allele C had greater SBP decrease during low-sodium intervention. Furthermore, a haplotype containing allele C was associated with greater SBP increase to high-sodium intervention ( P = 0.0009). Seven SNPs of ECE1 , one of the degrading enzymes of kinins, were significantly associated with diastolic BP (DBP) response to low-sodium intervention ( P values ranged from 0.0003 to 0.002). Two haplotypes in the linkage disequilibrium block including these seven SNPs were significantly associated with DBP response to low-sodium intervention (P=0.0004 and 0.003, respectively). Our study found that the genetic variants of the KKS were associated with salt sensitivity of BP. Replication and functional studies of the identified variants are warranted in the future.

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Abstract P262: Resequencing Study Identifies Epithelial Sodium Channel Genes and Novel Low Frequency Variants Associated with Blood Pressure Salt-sensitivity: The GenSalt Study

Circulation ◽

10.1161/circ.133.suppl_1.p262 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

Christopher E Anderson ◽

Changwei Li ◽

Jiang He ◽

Dongfeng Gu ◽

Dabeeru C Rao ◽

...

Keyword(s):

Blood Pressure ◽

Family Structure ◽

Sodium Channel ◽

Association Studies ◽

Low Frequency ◽

Epithelial Sodium Channel ◽

Salt Sensitivity ◽

Minor Allele ◽

Indicator Variable ◽

High Sodium

Christopher E. Anderson, Changwei Li, Jiang He, Dongfeng Gu, Dabeeru C. Rao, James E. Hixson, Lawrence C. Shimmin, Jianfeng Huang, Charles C. Gu, Jichun Chen, Jianxin Li, Tanika N. Kelly Genetic association studies have identified significant associations between common variants from the epithelial sodium channel (ENaC) genes and blood pressure responses to dietary sodium interventions. The roles of low-frequency and rare ENaC variants in blood pressure salt-sensitivity remain largely unexplored. To test this hypothesis, we conducted an ENaC candidate gene resequencing study among participants in the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt). The GenSalt study was conducted among 1,906 participants from 633 families who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium (307.8 mmol sodium/day) feeding-study. We chose the 300 GenSalt subjects with the highest and 300 GenSalt subjects with the lowest mean arterial pressure responses to the high sodium intervention to participate in the current resequencing study. Functional regions of three ENaC subunit genes ( SCNN1A , SCNN1B and SCNN1G ) were resequenced using the VariantSEQr TM system (Applied Biosystems; Foster City, CA). For gene-based analyses, variants with MAF less than 5% were first collapsed within each ENaC gene. The collapsed indicator variable was then tested for association with blood pressure salt-sensitivity using generalized estimating equations (GEE) to accommodate correlation of genotypes due to family structure and adjust for the fixed effects of age, gender and field center. Single variant analyses were performed for all low-frequency variants with a minor allele frequency (MAF) greater than 1% and less than 5%, again using GEE to accommodate family structure and adjust for covariables. We did not identify any associations between ENaC genes and blood pressure salt-sensitivity in the gene-based analyses. However, single variant analysis identified a novel association between a low-frequency variant in SCNN1G , rs148083677, and blood pressure salt-sensitivity (P=0.02). Each minor allele was associated with 71% lower odds of blood pressure salt-sensitivity. Although replication studies are needed, these findings provide promising evidence of a role for low-frequency ENaC variants in blood pressure salt-sensitivity.

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Effect of chloride on renal blood flow in angiotensin II induced hypertension

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y91-076 ◽

1991 ◽

Vol 69 (4) ◽

pp. 507-511 ◽

Cited By ~ 5

Author(s):

John C. Passmore ◽

Agnes E. Jimenez

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Sodium Chloride ◽

Angiotensin Ii ◽

Renal Blood Flow ◽

Dietary Sodium ◽

Maximum Increase ◽

High Sodium ◽

Low Sodium ◽

Chloride Effect

The effect of selective dietary sodium and (or) chloride loading on blood pressure and renal blood flow (RBF) in the rat angiotensin II (AII) model of hypertension was determined. AII (200 ng/min) or saline was infused intraperitoneally. Diets were provided with either high or low concentrations of sodium, chloride or both ions for 22 days. The blood pressure of saline-treated animals was not increased by the high sodium chloride diet. Animals on a high sodium, high chloride diet had a significantly greater increase of blood pressure at 8, 15, 18, and 22 days of AII infusion compared with AII-treated animals on a low sodium, low chloride diet (p < 0.05). Selective dietary loading of either high sodium or chloride in AII-treated rats produced no greater elevation of blood pressure than AII with the low sodium, low chloride diet. Selective high dietary chloride was associated with a lower RBF in AII- and vehicle-treated rats compared with low dietary chloride. The chloride effect on RBF was greater in AII-treated animals. In conclusion, both sodium and chloride are necessary to produce the maximum increase of blood pressure in AII animals. AII enhances the decreased RBF induced by dietary chloride.Key words: angiotensin II, sodium chloride, blood pressure.

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Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride

10.1002/14651858.cd004022.pub3 ◽

2011 ◽

Cited By ~ 48

Author(s):

Niels Albert Graudal ◽

Thorbjorn Hubeck-Graudal ◽

Gesche Jurgens

Keyword(s):

Blood Pressure ◽

High Sodium ◽

Sodium Diet ◽

Low Sodium Diet ◽

Low Sodium ◽

Diet Versus ◽

High Sodium Diet

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Abstract P010: D 1 R And D 5 R And Their Role In The Etiology Of Inverse Salt Sensitivity Of Blood Pressure

Hypertension ◽

10.1161/hyp.76.suppl_1.p010 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

John J Gildea ◽

Michael G Daley ◽

Peng Xu ◽

Katherine A Schiermeyer ◽

Wei Yue ◽

...

Keyword(s):

Blood Pressure ◽

Salt Sensitivity ◽

T Test ◽

Morbidity And Mortality ◽

The Novel ◽

Proximal Tubule Cells ◽

Mortality And Morbidity ◽

R And D ◽

Low Sodium ◽

Renal Proximal Tubule Cells

Cardiovascular studies show increased morbidity and mortality in individuals consuming low sodium diets as well as high salt diets. The incidence of salt sensitivity of blood pressure (SS) in normotensives is approximately 18%, causing similar mortality and morbidity as hypertensives. Paradoxically, approximately 15% of normotensives demonstrate an increase in blood pressure on low sodium diets, known as inverse salt sensitivity (ISS). However, little is known about the morbidity and mortality associated with ISS, let alone the mechanisms behind this condition. Since dopamine regulates up to 75% of renal sodium handling, we hypothesized that the dopamine 1 and 5 receptors (D1R, D5R) were involved with the etiology of ISS. Using renal proximal tubule cells (RPTC) isolated from salt diet participant’s urine exposed to 90 mM salt (NaCl) (2 hr), we demonstrated reduced binding of the non-cell permeable D1-like antagonist (D1R and D5R) bodipy-530 SKF83566 (Fl-SKF) in the ISS RPTC when compared to salt resistant (SR) RPTC (ISS -13.9 ± 3.8% vs SR -1.1 ± 3.2%, n=12, p<0.05, t-test). Incubation in 190 mM NaCl for 2 hours and overnight (ON) increased Fl-SKF binding only in the ISS RPTCs but not the SR RPTC when compared to 140 mM NaCl (NS) (ISS 2 Hours +16.6 ± 6.2% and ISS ON +12.0 ± 2.8%, n=12, p<0.05 vs NS, t-test). ON incubation in 90 mM NaCl reduced Fl-SKF binding in both ISS and SR RPTC (ISS -15.2 ± 2.9% and SR -16.3 ± 2.3%, n=12, p<0.01, vs NS, t-test), and this effect was completely blocked by co-incubation with the angiotensin type 1 receptor (AT1R) antagonist losartan (LOS, 1 uM). The decrease in Fl-SKF binding in 90 mM NaCl was attributed to the D5R, and an increase in FL-SKF binding in 190 mM NaCl was verified to be due to an increase in plasma membrane D1R expression using antibodies directed to extracellular epitopes. A D5R specific monoclonal antibody developed in-house binds to the third extracellular loop of this receptor in order to measure these receptors selectively. Continued studies will be conducted with these cell lines with D1R and D5R knocked down to determine specific roles these receptors have in the novel ISS phenotype.

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