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

Hypertension ◽  
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.

scholarly journals Salt Sensitivity of Blood Pressure Is Associated With Polymorphisms in the Sodium-Bicarbonate Cotransporter

Hypertension ◽  
2012 ◽  
Vol 60 (5) ◽  
pp. 1359-1366 ◽  
Author(s):  
Robert M. Carey ◽  
Cynthia D. Schoeffel ◽  
John J. Gildea ◽  
John E. Jones ◽  
Helen E. McGrath ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Bicarbonate ◽  
Salt Sensitivity ◽  
Sodium Bicarbonate Cotransporter

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

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Tanika N Kelly ◽  
Casey M Rebholz ◽  
Dongfeng Gu ◽  
James E Hixson ◽  
Dabeeru C Rao ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Estrogen Receptor ◽  
Sex Hormones ◽  
Heart Association ◽  
Complex Trait ◽  
Salt Sensitivity ◽  
Nucleotide Polymorphisms ◽  
High Sodium ◽  
Low Sodium ◽  
Estrogen Receptor 1

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)

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

Circulation ◽  
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.

Immunolocalization of electrogenic sodium-bicarbonate cotransporters pNBC1 and kNBC1 in the rat eye

2001 ◽  
Vol 281 (5) ◽  
pp. F920-F935 ◽  
Author(s):  
Dean Bok ◽  
Matthew J. Schibler ◽  
Alexander Pushkin ◽  
Pejvak Sassani ◽  
Natalia Abuladze ◽  
...  
Keyword(s):  
Protein Expression ◽  
Sodium Bicarbonate ◽  
Molecular Mechanisms ◽  
Coding Region ◽  
Sodium Bicarbonate Cotransporter ◽  
Band Keratopathy ◽  
Proximal Renal Tubular Acidosis ◽  
Renal Tubular ◽  
Protein Variants ◽  
Renal Phenotype

The human NBC1 gene encodes two electrogenic sodium-bicarbonate cotransport proteins, pNBC1 and kNBC1, which are candidate proteins for mediating electrogenic sodium-bicarbonate cotransport in ocular cells. Mutations in the coding region of the human NBC1 gene in exons common to both pNBC1 and kNBC1 result in a syndrome with a severe ocular and renal phenotype (blindness, band keratopathy, glaucoma, cataracts, and proximal renal tubular acidosis). In the present study, we determined the pattern of electrogenic sodium-bicarbonate cotransporter protein expression in rat eye. For this purpose, pNBC1- and kNBC1-specific antibodies were generated and used to detect these NBC1 protein variants by immunoblotting and immunocytochemistry. pNBC1 is expressed in cornea, conjunctiva, lens, ciliary body, and retina, whereas the expression of kNBC1 is restricted to the conjunctiva. These results provide the first evidence for extrarenal kNBC1 protein expression. The data in this study will serve as a basis for understanding the molecular mechanisms responsible for abnormalities in ocular electrogenic sodium-bicarbonate cotransport in patients with mutations in the NBC1 gene.

scholarly journals Effects of environmental and genetic risk factors for salt sensitivity on blood pressure in northern China: the systemic epidemiology of salt sensitivity (EpiSS) cohort study

BMJ Open ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. e023042 ◽  
Author(s):  
Han Qi ◽  
Bin Liu ◽  
Chunyue Guo ◽  
Zheng Liu ◽  
Han Cao ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Northern China ◽  
Salt Sensitivity ◽  
Urine Samples ◽  
Liaoning Province ◽  
Nucleotide Polymorphisms ◽  
Spot Urine ◽  
Face To Face ◽  
Non Coding Rnas

PurposeThe systemic epidemiology of salt sensitivity (EpiSS) study aims to combine molecular biology, epidemiology and bioinformatics methods to discover the potential causes of salt sensitivity of blood pressure (SSBP) using single-nucleotide polymorphisms in the genome and non-coding RNAs in the transcriptome to uncover both the genetic and environmental factors of SSBP.ParticipantsBetween July 2014 and July 2016, we enrolled adults from 11 study centres in Beijing and Liaoning Province; participants were of the Han population and were 35–70 years of age. We collected blood samples, spot urine samples and 24-hour urine samples, in addition to baseline data on demographics, health-related lifestyle factors, chronic diseases, family history of illness and anthropometric information through face-to-face interviews using a standardised questionnaire. EpiSS uses the modified Sullivan’s acute oral saline load and diuresis shrinkage test (MSAOSL-DST) to evaluate the effects of salt on blood pressure.Findings to dateIn total, 2163 participants were included in the EpiSS, of which 2144 participants completed the questionnaire, 2120 (98.0%) completed the MSAOSL-DST and 2083 (96.3%) provided a 24-hour urine sample. A total of 2057 participants (1501 women and 556 men) completed all the steps of the investigation and were included in the analysis. Among them, 583 (28.3%) subjects were classified as having salt sensitivity of blood pressure, and 1061 (51.6%) had hypertension.Future plansThe next step of our study is to evaluate the incidence of cardiovascular disease in the participants. Biennial follow-up, including face-to-face questionnaire surveys, laboratory measurements of blood, urinary creatinine, glomerular filtration rate and anthropometric measurements, will occur two additional times. DNA and RNA will be collected for subsequent genetic biomarker studies. We plan on screening the salt-sensitive-related gene loci and non-coding RNAs based on relative environmental risk factors.Trial registration numberChiCTR-EOC-16009980; Pre-results.

Abstract MP09: Effect Of Western Diet On Renal Transcriptome Of Hypertensive Mice Overexpressing Human Angiotensin Receptor Type 1

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Harshada Ketkar ◽  
Samantha Tang ◽  
Sudhir Jain
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
Renal Tissue ◽  
Western Diet ◽  
Rna Seq ◽  
Angiotensin Ii Receptor ◽  
Regular Diet ◽  
Aged Mice ◽  
Specific Regulation ◽  
Renal Tubular

Over-expression of human angiotensin-II receptor type1 (hAT1R) may cause pathological outcomes due to overactivation of renin-angiotensin system. Transgenic (TG) mice containing Hap-I (hypertensive genotype) of human hAT1R gene are more prone to develop metabolic syndrome disorders as compared to TG mice with Hap-II (normotensive genotype). This gene variant associated risk of hypertension together with Western diet and aging may lead to renal disorders. However, mechanisms underlying this process are not well examined. For this purpose, we studied the renal gene expression alterations in aged TG mice containing either Hap-I or Hap-II of hAT1R gene. Aged mice (20-24 months of age) were maintained on a regular diet or high fat diet with 2% NaCl (Western diet, WD) for 16 weeks. On a regular diet, aged Hap-I mice presented higher (~9 mmHg) systolic blood pressure with respect to age-matched Hap-II animals. Following administration of Western diet, blood pressure increased in both groups of mice, but to a larger extent in Hap-I animals (~15 mmHg in comparison to ~7 mmHg in Hap-II). Aged Hap-I mice on Western diet showed increased renal fibrosis. RNA-seq data from renal tissue of Hap-I aged mice revealed that WD significantly altered the expression of >400 genes (p-adj. <0.05). Bioinformatics analysis (Qiagen IPA software) identified major alterations in main canonical pathways involved in renal function and oxidative damage. These changes in turn resulted in kidney failure, renal tubular injury, and renal proliferation. In addition, post WD treatment, RNA seq. analysis from Hap-I and Hap-II kidneys also reveals haplotype specific regulation of genes associated with blood pressure regulation and kidney disorders. Overall, these results indicate that Western diet promotes hypertension and fibrosis in the kidneys of aged mice. These alterations are paralleled by perturbation of renal transcriptional profile. Overall, these studies will assist in the identification of novel mechanisms and molecules involved in hypertension and associated kidney pathophysiology.

Abstract MP15: Single And Joint Associations Of Genetic Variants In The Serum/glucocorticoid Regulated Kinase (sgk) Genes With Blood Pressure Responses To Sodium Intake: The Gensalt Study

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Changwei Li ◽  
Xueli Yang ◽  
Jiang He ◽  
James E Hixson ◽  
Dongfeng Gu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Multiple Testing ◽  
Sodium Intake ◽  
Critical Role ◽  
Salt Sensitivity ◽  
P Value ◽  
Association Analyses ◽  
High Sodium ◽  
Single Marker ◽  
Blood Pressure Responses

Background: Serum and glucocorticoid regulated kinase (SGK) plays a critical role in the regulation of renal sodium transport. We examined the association between SGK genes and salt sensitivity of blood pressure (BP) using single-marker and gene-based association analyses. Methods: A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) was conducted among 1,906 Chinese participants. BP measurements were obtained at baseline and each intervention using a random-zero sphygmomanometer. Additive associations between each SNP and salt-sensitivity phenotypes were assessed using a mixed linear regression model to account for family dependencies. Gene-based analyses were conducted using the truncated p-value method. The Bonferroni-method was used to adjust for multiple testing in all analyses. Results: In single-marker association analyses, SGK1 marker rs2758151 was significantly associated with diastolic BP (DBP) response to high-sodium intervention (P=0.0010). DBP responses (95% confidence interval) to high-sodium intervention for genotypes C/C, C/T, and T/T were 2.04 (1.57 to 2.52), 1.79 (1.42 to 2.16), and 0.85 (0.30 to 1.41) mmHg, respectively. Similar non-significant trends were observed for SBP and MAP responses (P=0.15 and 0.0026, respectively). In addition, gene-based analyses demonstrated significant associations between SGK1 and SBP, DBP and MAP responses to high sodium intervention (P=0.0002, 0.0076, and 0.00001, respectively). Neither SGK2 nor SGK3 were associated with the salt-sensitivity phenotypes in single-maker and gene-based analyses. Conclusions: The current study identified single-marker and gene-based association of the SGK1 gene and BP salt-sensitivity in the Han Chinese population. Further studies are warranted to identify causal SGK1 gene variants.

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