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 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 Urinary sodium excretion and the risk of cardiovascular disease: A community-based cohort study in Taiwan

2021 ◽  
pp. 1-42
Author(s):  
Yi-Jie Wang ◽  
Kuo-Lioug Chien ◽  
Hsiu-Ching Hsu ◽  
Hung-Ju Lin ◽  
Ta-Chen Su ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Systolic Blood Pressure ◽  
Sodium Excretion ◽  
Urinary Sodium Excretion ◽  
Salt Sensitivity ◽  
Urinary Sodium ◽  
Mediating Effect ◽  
Cvd Risk ◽  
Media Thickness

Abstract Urinary sodium excretion is a potential risk factor for cardiovascular diseases (CVD). However, the underlying biological mechanisms and effects of salt sensitivity are unclear. The purpose of this study was to characterize the relative contribution of biological factors to the sodium-CVD association. A total of 2112 participants were enrolled in this study. Structured questionnaires and blood and urine samples were obtained. Twenty-four-hour sodium excretion was estimated using a single overnight urine sample. Hypertension, metabolic syndrome, and overweight status were considered to indicate salt sensitivity. Cox proportional hazard models were used to investigate the effects of salt sensitivity on urinary sodium excretion and CVD risk. The traditional mediation approach was used to calculate the proportion of mediation. The mean age (standard deviation) of the 2112 participants was 54.5 (12.2) years, and they were followed up for a mean of 14.1 [8.1] years. Compared with those in the lowest quartile, the highest baseline urinary sodium excretion (>4.2g/24 hours) was associated with a 43% higher CVD risk (hazard ratio, 1.43; 95% confidence interval, 1.02-1.99). Participants with high urinary sodium excretion, hypertension, or metabolic syndrome had a significantly high risk of CVD. The carotid intima-media thickness had the largest mediating effect (accounting for 35% of the sodium-CVD association), followed by systolic blood pressure (33%), left ventricular mass (28%), and diastolic blood pressure (14%). Higher urinary sodium excretion increased the risk of CVD, which was explained largely by carotid media-thickness and systolic blood pressure.

Abstract 101: Tissue-specific Deletion of Collectrin in the Proximal Tubular Epithelium Increases Arterial Pressure and Augments Salt-sensitivity

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Sylvia Cechova ◽  
Pei-Lun Chu ◽  
Joseph C Gigliotti ◽  
Fan Chan ◽  
Thu H Le
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Renal Blood Flow ◽  
Collecting Duct ◽  
Critical Role ◽  
Specific Effect ◽  
Salt Sensitivity ◽  
Kidney Cortex ◽  
Mrna Levels ◽  
Proximal Tubular

Background: Collectrin ( Tmem27 ) is a key regulator of blood pressure (BP) and modulator of the bioavailability of nitric oxide (NO) and superoxide. It is highly expressed in the kidney in the proximal tubule (PT), collecting duct, and throughout the vascular endothelium. We reported that collectrin plays a critical role as a chaperone for the reabsorption of all amino acids (AAs) in the PT, and for the uptake of the cationic AA L-arginine (L-Arg) in endothelial cells. Global collectrin knockout ( Tmem27 Y/- ) mice display baseline hypertension (HTN), augmented salt-sensitive hypertension (SSH), and decreased renal blood flow. Objective and Methods: To determine the PT-specific effect of collectrin on BP homeostasis and salt sensitivity, we used the Cre -loxP approach and PEPCK-Cre to generate a mouse line lacking collectrin specifically in the PT-- PEPCK-Cre + Tmem27 Y/Flox mice. PEPCK-Cre - Tmem27 Y/Flox mice were used as control. Radiotelemetry was used to measure BP for 2 weeks at baseline and 2 weeks on high salt diet (HSD). Renal blood flow at baseline and on HSD was measured using contrast enhanced ultrasound in the same mice. Results: Successful deletion of collectrin in the PT was confirmed by assessing mRNA levels using real-time RT-PCR, immunohistochemistry staining of renal tissues using anti-collectrin antibody, and quantitation of protein from kidney cortex by Western analysis. Compared to control PEPCK-Cre - Tmem27 Y/Flox mice (n=6), PEPCK-Cre + Tmem27 Y/Flox mice (n=6) displayed significantly higher systolic BP (SBP) at baseline (120.0 ± 2.5 vs 131.6 ± 2.9 mm Hg; p = 0.014) and after HSD (135.3 ± 2.6 vs 151.5 ± 5.2 mm Hg; p = 0.019). Renal blood flow was not different between groups, at baseline nor after HSD. Conclusion: Collectrin in the PT plays an important role in blood pressure homeostasis and response to sodium intake, independent of renal blood flow. Increasing proximal tubular collectrin activity may be a novel therapeutic strategy for the treatment of hypertension and salt-sensitivity.

Abstract 356: A Role for Renal Proximal Tubule Sodium Bicarbonate Cotransporter SLC4A5 in Salt-Sensitivity of Blood Pressure

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Julia M Carlson ◽  
John J Gildea ◽  
Helen E McGrath ◽  
Robin A Felder
Keyword(s):  
Sodium Bicarbonate ◽  
Proximal Tubule ◽  
Mrna Expression ◽  
Cell Lines ◽  
Renin Angiotensin System ◽  
Salt Sensitivity ◽  
Renal Proximal Tubule ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Homozygous Variant

SLC4A5 is a sodium-bicarbonate co-transporter involved with sodium homeostasis. Based on unpublished data, two SLC4A5 single nucleotide polymorphisms (SNPs rs1017783 and rs7571842) have been highly associated with an individual’s salt-sensitivity status. Since the renal proximal tubule (RPT) regulates a large percentage of renal sodium transport, we investigated whether SLC4A5 was present in this nephron segment. Using confocal immunofluorescence microscopy, we found expression of SLC4A5 in human RPT cell plasma membrane and intracellular membrane vesicles. We then examined the physiologic implications of the SLC4A5 SNPs in human RPT cells. Using immunoblotting and RT-PCR, we found no significant differences in basal SLC4A5 expression in RPT cells between individuals that are homozygous variant at both SNPs and individuals that are wild-type (WT) for both alleles. Stimulation of the dopaminergic system with 1μM fenoldopam, or the renin-angiotensin system with 10 nM angiotensin II or 10 nM angiotensin III (n=18 per treatment) over 3 and 24 hours did not significantly alter SLC4A5 protein or 24 hour mRNA expression. These data indicate that SLC4A5 is not directly regulated by either the renal dopaminergic or renin-angiotensin system. However, 24 hour stimulation with the sodium ionophore monensin (MON, 1μM) significantly increased overall mRNA expression of SLC4A5 by 182±0.098% over vehicle (VEH) (ΔCq VEH=0.283±0.035; n=18, p<0.001). There was also a significant increase in SLC4A5 mRNA in three cell lines homozygous variant for both alleles compared to three WT cell lines following MON treatment at both 3 hours (138±0.10%; ΔCq WT MON = 0.5±0.052; n=9, p<0.05) and 24 hours (161±0.11%; ΔCq WT MON = 0.39±0.066; n=9, p<0.02). Three but not 24 hour stimulation with MON also significantly increased overall expression of SLC4A5 protein (137±0.00041%; RFU VEH=0.0030±0.00022; n=18, p<0.01). MON, by allowing salt to enter a cell, may be activating an enhancer that leads to increased transcription of SLC4A5 mRNA that is more effective in homozygous variant cell lines. These novel observations demonstrate that SNPs located in a non-promoter DNA intron are associated with enhanced promoter activity that is regulated by altered intracellular sodium.

Renal denervation alters ambulatory blood pressure-derived salt sensitivity index in patients with uncontrolled hypertension

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Revathy Carnagarin ◽  
Janis M. Nolde ◽  
Rebecca Lee ◽  
Leslie Marisol Lugo-Gavidia ◽  
Natalie C. Ward ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Ambulatory Blood Pressure ◽  
Renal Denervation ◽  
Salt Sensitivity ◽  
Uncontrolled Hypertension ◽  
Sensitivity Index

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.

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