scholarly journals A Mouse Model for Liddle's Syndrome

1999 ◽  
Vol 10 (12) ◽  
pp. 2527-2533 ◽  
Author(s):  
SYLVAIN PRADERVAND ◽  
QING WANG ◽  
MICHEL BURNIER ◽  
FRIEDRICH BEERMANN ◽  
JEAN DANIEL HORISBERGER ◽  
...  
Keyword(s):  
Mouse Model ◽  
Salt Intake ◽  
Sodium Reabsorption ◽  
Dietary Salt ◽  
Human Form ◽  
Dominant Form ◽  
Liddle’S Syndrome ◽  
High Salt Intake ◽  
Liddle's Syndrome ◽  
Salt Sensitive Hypertension

Abstract. Liddle's syndrome (or pseudoaldosteronism) is an autosomal dominant form of salt-sensitive hypertension, due to abnormal sodium transport by the renal tubule. To study the pathophysiology of salt sensitivity, a mouse model for Liddle's syndrome has been generated by Cre/loxP-mediated recombination. Under normal salt diet, mice heterozygous (L/+) and homozygous (L/L) for Liddle mutation (L) develop normally during the first 3 mo of life. In these mice, BP is not different from wild type despite evidence for increased sodium reabsorption in distal colon and low plasma aldosterone, suggesting chronic hypervolemia. Under high salt intake, the Liddle mice develop high BP, metabolic alkalosis, and hypokalemia accompanied by cardiac and renal hypertrophy. This animal model reproduces to a large extent a human form of salt-sensitive hypertension and establishes a causal relationship between dietary salt, a gene expressed in kidney and hypertension.

scholarly journals Test of the hypothesis that eating high-salt food leads to obesity by stimulating sugar-solution consumption

2020 ◽  
Author(s):  
Genevieve Alexandria Bell ◽  
Hillary Ellis ◽  
Michael Tordoff
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Energy Intake ◽  
Salt Intake ◽  
Salt Content ◽  
High Salt ◽  
Sugar Solution ◽  
Dietary Salt ◽  
Salt Diet ◽  
High Salt Intake

High salt intake has been linked to obesity in humans and rodents, although the direction of causation and underlying mechanisms are unclear. One hypothesis suggests that consuming salt stimulates thirst, which is assuaged by drinking sugar-sweetened beverages, leading to excess energy intake and thus obesity. We attempted to test this hypothesis using a mouse model. Adult male C57BL/6J mice ate semi-synthetic diets with either low (0.56 g Na+/kg diet) or high (5.62 g Na+/kg diet) salt content for 8 weeks. Half the mice fed each diet could drink water; the other half could drink both water and a 16% sucrose solution. Mice fed the high-salt diet with water to drink ingested ~25% more water than did those fed the low-salt diet with water to drink, demonstrating that salt stimulated thirst. However, there was no influence of dietary salt on water or sucrose intake in the groups with access to both water and sucrose. This was probably because sucrose intakes were near-maximal in both groups; mice apparently do not require salt to encourage them to drink sucrose. Dietary salt level had no effect on body weight. Relative to mice that drank only water, those that drank sucrose had a net increase in energy intake but, surprisingly, gained less body weight, perhaps because they consumed too little protein to thrive. In sum, our results do not support the hypothesis that salt increases sugar-sweetened beverage consumption, leading to obesity; however, the simple mouse model used here may not provide a competent test of this hypothesis.

scholarly journals Epithelial Sodium Channel and Salt-Sensitive Hypertension

Hypertension ◽  
2021 ◽  
Vol 77 (3) ◽  
pp. 759-767
Author(s):  
Stephanie M. Mutchler ◽  
Annet Kirabo ◽  
Thomas R. Kleyman
Keyword(s):  
Blood Pressure ◽  
Sodium Channel ◽  
Salt Intake ◽  
Extracellular Fluid ◽  
Pressure Rise ◽  
Epithelial Sodium Channel ◽  
Sodium Reabsorption ◽  
High Salt Intake ◽  
Salt Sensitive Hypertension

The development of high blood pressure is influenced by genetic and environmental factors, with high salt intake being a known environmental contributor. Humans display a spectrum of sodium-sensitivity, with some individuals displaying a significant blood pressure rise in response to increased sodium intake while others experience almost no change. These differences are, in part, attributable to genetic variation in pathways involved in sodium handling and excretion. ENaC (epithelial sodium channel) is one of the key transporters responsible for the reabsorption of sodium in the distal nephron. This channel has an important role in the regulation of extracellular fluid volume and consequently blood pressure. Herein, we review the role of ENaC in the development of salt-sensitive hypertension, and present mechanistic insights into the regulation of ENaC activity and how it may accelerate sodium-induced damage and dysfunction. We discuss the traditional role of ENaC in renal sodium reabsorption and review work addressing ENaC expression and function in the brain, vasculature, and immune cells, and how this has expanded the implications for its role in the initiation and progression of salt-sensitive hypertension.

scholarly journals Sympathetic Regulation of the NCC (Sodium Chloride Cotransporter) in Dahl Salt–Sensitive Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (5) ◽  
pp. 1461-1469
Author(s):  
Franco Puleo ◽  
Kiyoung Kim ◽  
Alissa A. Frame ◽  
Kathryn R. Walsh ◽  
Mohammed Z. Ferdaus ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Chloride ◽  
Salt Intake ◽  
High Salt ◽  
Sodium Reabsorption ◽  
Sprague Dawley ◽  
Sodium Chloride Cotransporter ◽  
High Salt Intake ◽  
Sympathetic Regulation ◽  
Salt Sensitive Hypertension

Increased sympathoexcitation and renal sodium retention during high salt intake are hallmarks of the salt sensitivity of blood pressure. The mechanism(s) by which excessive sympathetic nervous system release of norepinephrine influences renal sodium reabsorption is unclear. However, studies demonstrate that norepinephrine can stimulate the activity of the NCC (sodium chloride cotransporter) and promote the development of SSH (salt-sensitive hypertension). The adrenergic signaling pathways governing NCC activity remain a significant source of controversy with opposing studies suggesting a central role of upstream α 1 - and β-adrenoceptors in the canonical regulatory pathway involving WNKs (with-no-lysine kinases), SPAK (STE20/SPS1-related proline alanine-rich kinase), and OxSR1 (oxidative stress response 1). In our previous study, α 1 -adrenoceptor antagonism in norepinephrine-infused male Sprague-Dawley rats prevented the development of norepinephrine-evoked SSH in part by suppressing NCC activity and expression. In these studies, we used selective adrenoceptor antagonism in male Dahl salt–sensitive rats to test the hypothesis that norepinephrine-mediated activation of the NCC in Dahl SSH occurs via an α 1 -adrenoceptor dependent pathway. A high-salt diet evoked significant increases in NCC activity, expression, and phosphorylation in Dahl salt–sensitive rats that developed SSH. Increases were associated with a dysfunctional WNK1/4 dynamic and a failure to suppress SPAK/OxSR1 activity. α 1 -adrenoceptor antagonism initiated before high-salt intake or following the establishment of SSH attenuated blood pressure in part by suppressing NCC activity, expression, and phosphorylation. Collectively, our findings support the existence of a norepinephrine-activated α 1 -adrenoceptor gated pathway that relies on WNK/SPAK/OxSR1 signaling to regulate NCC activity in SSH.

scholarly journals Chronic glucose infusion causes sustained increases in tubular sodium reabsorption and renal blood flow in dogs

2009 ◽  
Vol 296 (2) ◽  
pp. R265-R271 ◽  
Author(s):  
Michael W. Brands ◽  
Tracy D. Bell ◽  
Nancy A. Rodriquez ◽  
Praveen Polavarapu ◽  
Dmitriy Panteleyev
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Salt Intake ◽  
Plasma Renin ◽  
Urinary Sodium Excretion ◽  
Glucose Infusion ◽  
Sodium Reabsorption ◽  
Tubular Sodium Reabsorption ◽  
High Salt Intake ◽  
Sustained Increase

This study tested the hypothesis that inducing hyperinsulinemia and hyperglycemia in dogs, by infusing glucose chronically intravenously, would increase tubular sodium reabsorption and cause hypertension. Glucose was infused for 6 days (14 mg·kg−1·min−1 iv) in five uninephrectomized (UNX) dogs. Mean arterial pressure (MAP) and renal blood flow (RBF) were measured 18 h/day using DSI pressure units and Transonic flow probes, respectively. Urinary sodium excretion (UNaV) decreased significantly on day 1 and remained decreased over the 6 days, coupled with a significant, sustained increase in RBF, averaging ∼20% above control on day 6. Glomerular filtration rate and plasma renin activity (PRA) also increased. However, although MAP tended to increase, this was not statistically significant. Therefore, the glucose infusion was repeated in six dogs with 70% surgical reduction in kidney mass (RKM) and high salt intake. Blood glucose and plasma insulin increased similar to the UNX dogs, and there was significant sodium retention, but MAP still did not increase. Interestingly, the increases in PRA and RBF were prevented in the RKM dogs. The decrease in UNaV, increased RBF, and slightly elevated MAP show that glucose infusion in dogs caused a sustained increase in tubular sodium reabsorption by a mechanism independent of pressure natriuresis. The accompanying increase in PRA, together with the failure of either RBF or PRA to increase in the RKM dogs, suggests the site of tubular reabsorption was before the macula densa. However, the volume retention and peripheral edema suggest that systemic vasodilation offsets any potential renal actions to increase MAP in this experimental model in dogs.

Enhanced sympathoexcitatory and pressor responses to central Na+ in Dahl salt-sensitive vs. -resistant rats

2001 ◽  
Vol 281 (5) ◽  
pp. H1881-H1889 ◽  
Author(s):  
Bing S. Huang ◽  
Hao Wang ◽  
Frans H. H. Leenen
Keyword(s):  
Wistar Rats ◽  
Salt Intake ◽  
Baroreflex Control ◽  
Renal Sympathetic Nerve Activity ◽  
Intracerebroventricular Infusion ◽  
Air Jet ◽  
Adrenoceptor Agonist ◽  
Pressor Responses ◽  
High Salt Intake ◽  
Salt Sensitive Hypertension

An enhanced responsiveness to increases in cerebrospinal fluid (CSF) Na+ by high salt intake may contribute to salt-sensitive hypertension in Dahl salt-sensitive (S) rats. To test this hypothesis, sympathetic and pressor responses to acute and chronic increases in CSF Na+were evaluated. In conscious young (5–6 wk old) and adult (10–11 wk old) Dahl S and salt-resistant (R) rats as well as weight-matched Wistar rats, hemodynamic [blood pressure (BP) and heart rate (HR)] and sympathetic [renal sympathetic nerve activity (RSNA)] responses to 10-min intracerebroventricular infusions of artificial CSF (aCSF) and Na+-rich aCSF (containing 0.2–0.45 M Na+) were evaluated. Intracerebroventricular Na+-rich aCSF increased BP, RSNA, and HR in a dose-related manner. The extent of these increases was significantly larger in Dahl S versus Dahl R or Wistar rats and young versus adult Dahl S rats. In a second set of experiments, young Dahl S and R rats received a chronic intracerebroventricular infusion of aCSF or Na+-rich (0.8 M) aCSF (5 μl/h) for 14 days, with the use of osmotic minipumps. On day 14 in conscious rats, CSF was sampled and BP, HR, and RSNA were recorded at rest and in response to air stress, intracerebroventricular α2-adrenoceptor agonist guanabenz, intracerebroventricular ouabain, and intravenous phenylephrine and nitroprusside to estimate baroreflex function. The infusion of Na+-rich aCSF versus aCSF increased CSF Na+ concentration to the same extent but caused severe versus mild hypertension in Dahl S and Dahl R rats, respectively. After central Na+ loading, hypothalamus “ouabain” significantly increased in Dahl S and only tended to increase in Dahl R rats. Moreover, sympathoexcitatory and pressor responses to intracerebroventricular exogenous ouabain were attenuated by Na+-rich aCSF to a greater extent in Dahl S versus Dahl R rats. Responses to air-jet stress or intracerebroventricular guanabenz were enhanced by Na+-rich aCSF in both strains, but the extent of enhancement was significantly larger in Dahl S versus Dahl R. Na+-rich aCSF impaired arterial baroreflex control of RSNA more markedly in Dahl S versus R rats. These findings indicate that genetic control of mechanisms linking CSF Na+ with brain “ouabain” is altered in Dahl S rats toward sympathetic hyperactivity and hypertension.

Limitation of arteriolar myogenic activity by local nitric oxide: segment-specific effect of dietary salt

1999 ◽  
Vol 277 (5) ◽  
pp. H1946-H1955 ◽  
Author(s):  
Timothy R. Nurkiewicz ◽  
Matthew A. Boegehold
Keyword(s):  
Nitric Oxide ◽  
Salt Intake ◽  
Specific Effect ◽  
High Salt ◽  
Myogenic Response ◽  
Dietary Salt ◽  
No Donor ◽  
Spontaneously Hypertensive ◽  
High Salt Intake ◽  
Wistar Kyoto

The purpose of this study was to determine if local nitric oxide (NO) activity attenuates the arteriolar myogenic response in rat spinotrapezius muscle. We also investigated the possibility that hypertension, dietary salt, or their combination can alter any influence of local NO on the myogenic response. Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) fed low-salt (0.45%, LS) or high-salt (7%, HS) diets were enclosed in a ventilated airtight box with the spinotrapezius muscle exteriorized for intravital microscopy. Mean arterial pressure was unaffected by dietary salt in WKY but was significantly higher and augmented by dietary salt in SHR. In all experiments, elevation of microvascular pressure by box pressurization caused a 0–30% decrease in the diameter of large (arcade bridge) arterioles and a 21–27% decrease in the diameter of intermediate (arcade) arterioles. Inhibition of NO synthase with N G-monomethyl-l-arginine (l-NMMA) significantly enhanced myogenic responsiveness of arcade bridge arterioles in WKY-LS and SHR-LS but not in WKY-HS and SHR-HS.l-NMMA significantly enhanced the myogenic responsiveness of arcade arterioles in all four groups. Excess l-arginine reversed this effect of l-NMMA in all cases, and arteriolar responsiveness to the NO donor sodium nitroprusside was not different among the four groups. High-salt intake had no effect on the passive distension of arterioles in either strain during box pressurization. We conclude that 1) local NO normally attenuates arteriolar myogenic responsiveness in WKY and SHR, 2) dietary salt impairs local NO activity in arcade bridge arterioles of both strains, and 3) passive arteriolar distensibility is not altered by a high-salt diet in either strain.

scholarly journals High Salt Intake Increases Copeptin but Salt Sensitivity Is Associated with Fluid Induced Reduction of Copeptin in Women

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Irina Tasevska ◽  
Sofia Enhörning ◽  
Philippe Burri ◽  
Olle Melander
Keyword(s):  
Body Weight ◽  
Salt Intake ◽  
Salt Sensitivity ◽  
High Salt ◽  
Dietary Salt ◽  
Urinary Volume ◽  
Salt Consumption ◽  
High Salt Intake ◽  
Low Salt ◽  
Induced Changes

This study investigated if copeptin is affected by high salt intake and whether any salt-induced changes in copeptin are related to the degree of salt sensitivity. The study was performed on 20 men and 19 women. In addition to meals containing 50 mmol NaCl daily, capsules containing 100 mmol NaCl and corresponding placebo capsules were administered during 4 weeks each, in random order. Measurements of 24 h blood pressure, body weight, 24 h urinary volume, and fasting plasma copeptin were performed at high and low salt consumption. Copeptin increased after a high compared to low dietary salt consumption in all subjects 3,59 ± 2,28 versus 3,12 ± 1,95 (P= 0,02). Copeptin correlated inversely with urinary volume, at both low (r= −0,42;P= 0,001) and high (r= −0,60;P< 0,001) salt consumption, as well as with the change in body weight (r= −0,53;P< 0,001). Systolic salt sensitivity was inversely correlated with salt-induced changes of copeptin, only in females (r= −0,58;P= 0,017). As suppression of copeptin on high versus low salt intake was associated with systolic salt sensitivity in women, our data suggest that high fluid intake and fluid retention may contribute to salt sensitivity.

scholarly journals Genetically, dietary sodium intake is causally associated with salt-sensitive hypertension risk in a community-based cohort study: a Mendelian randomization approach

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J.R Choi
Keyword(s):  
Mendelian Randomization ◽  
Salt Intake ◽  
Sodium Intake ◽  
Dietary Sodium ◽  
Funding Source ◽  
Dietary Salt ◽  
Community Based ◽  
Dietary Salt Intake ◽  
Hypertension Risk ◽  
Salt Sensitive Hypertension

Abstract   Excessive dietary salt intake is associated with an increased risk of hypertension. Salt sensitivity, i.e., an elevation in blood pressure in response to high dietary salt intake, has been associated with a high risk of cardiovascular disease and mortality. We investigated whether a causal association exists between dietary sodium intake and hypertension risk using Mendelian randomization (MR). We performed an MR study using data from a large genome-wide association study comprising 15,034 Korean adults in a community-based cohort study. A total of 1,282 candidate single nucleotide polymorphisms associated with dietary sodium intake, such as rs2960306, rs4343, and rs1937671, were selected as instrumental variables. The inverse variance weighted method was used to assess the evidence for causality. Higher dietary sodium intake was associated with salt-sensitive hypertension risk. The variants of SLC8E1 rs2241543 and ADD1 rs16843589 were strongly associated with increased blood pressure. In the logistic regression model, after adjusting for age, gender, smoking, drinking, exercise, and body mass index, the GRK4 rs2960306TT genotype was inversely associated with hypertension risk (OR = 0.356, 95% CI = 0.236–0.476). However, the 2350GG genotype (ACE rs4343) exhibited a 2.11-fold increased hypertension risk (OR = 2.114, 95% CI = 2.004–2.224) relative to carriers of the 2350AA genotype, after adjusting for confounders. MR analysis revealed that the odds ratio for hypertension per 1 mg/day increment of dietary sodium intake was 2.24 in participants with the PRKG1 rs12414562 AA genotype. Our findings suggest that dietary sodium intake may be causally associated with hypertension risk. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2017R1D1A3B03034119, 2014M3C9A3064552), and the KRIBB Initiative program. This research was also supported by the Medical Research Center Program (2017R1A5A2015369). This work was supported (in part) by the Yonsei University Research Fund 2017. Bioresources for this study were provided by the National Biobank of Korea and the Centers for Disease Control and Prevention, Republic of Korea (2017-009).

scholarly journals A Family with Liddle’s Syndrome Caused by a New Missense Mutation in the β Subunit of the Epithelial Sodium Channel

1998 ◽  
Vol 83 (6) ◽  
pp. 2210-2213 ◽  
Author(s):  
Junnosuke Inoue ◽  
Taisuke Iwaoka ◽  
Hiroshi Tokunaga ◽  
Kazufumi Takamune ◽  
Shojiro Naomi ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Missense Mutation ◽  
Sodium Current ◽  
Epithelial Sodium Channel ◽  
Missense Mutations ◽  
Β Subunit ◽  
Dominant Form ◽  
Liddle’S Syndrome ◽  
Liddle's Syndrome ◽  
Py Motif

Liddle’s syndrome is an autosomal dominant form of salt sensitive hypertension caused by mutations in the β or γ subunit of the epithelial sodium channel. Systemic mutagenesis studies revealed that a conserved PPPXY sequence (PY motif) of the C-terminus of the α, β, or γ subunits might be involved in the regulation of the channel activity. However, only two missense mutations in the PY motif of theβ subunit have been reported to cause Liddle’s syndrome. We sequenced the C-termini of the β and γ subunits of the epithelial sodium channel in a Japanese family clinically diagnosed as having Liddle’s syndrome and found a new missense mutation in the PY motif of the β subunit, P615S. Expression studies with P615S mutant in Xenopus oocytes resulted in an about 3-fold increase in the amiloride-sensitive sodium current compared to the wild type (p = 0.001). These findings provide further clinical evidence for the hypothesis that a conserved PY motif may be critically important for the regulation of the epithelial sodium channel.

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