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 Role of the epithelial sodium channel in salt-sensitive hypertension

2011 ◽  
Vol 32 (6) ◽  
pp. 789-797 ◽  
Author(s):  
Yan Sun ◽  
Jia-ning Zhang ◽  
Dan Zhao ◽  
Qiu-shi Wang ◽  
Yu-chun Gu ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Salt Sensitive Hypertension

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.

Possible Involvement of Up-regulated Salt Dependent Glucose Transporter-5 (SGLT5) in High-fructose Diet-induced Hypertension

2021 ◽  
Author(s):  
Hiroaki Hara ◽  
Kaori Takayanagi ◽  
Taisuke Shimizu ◽  
Takatsugu Iwashita ◽  
Akira Ikari ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Salt Intake ◽  
Extracellular Fluid ◽  
Sodium Reabsorption ◽  
High Fructose Diet ◽  
Fructose Metabolism ◽  
High Fructose ◽  
Induced Hypertension ◽  
Underlying Mechanisms ◽  
Salt Sensitive Hypertension

Abstract Excessive fructose intake causes a variety of adverse conditions (e.g., obesity, hepatic steatosis, insulin resistance and uric acid overproduction). Particularly, high fructose-induced hypertension is the most common and significant pathological setting, however, its underlying mechanisms are not established. We investigated these mechanisms in 7-week-old male SD rats fed a diet containing 60% glucose (GLU) or 60% fructose (FRU) for 3, 6, or 12 weeks. Daily food consumption was measured to avoid between-group discrepancies in caloric/salt intake, adjusting for feeding amounts. The FRU rats' mean blood pressure was significantly higher and fractional sodium excretion (FENa) was significantly lower, indicating that the high-fructose diet caused salt retention. The FRU rats' kidney weight and glomerular surface area were greater, suggesting that the high-fructose diet induced an increase in extracellular fluid volume. The GLUT5 and ketohexokinase expressions, an enzyme required for fructose metabolism, were up-regulated in FRU. Cortical ATP levels were significantly lower in FRU, which might indicate ATP consumption due to fructose metabolism. Unlike previous reports, the high-fructose diet did not affect NHE3 expression. A gene chip analysis conducted to identify susceptible molecules revealed that only Slc5a10 (corresponding to SGLT5) in FRU showed >2-fold up-regulation versus GLU. RT-PCR and in situ hybridization confirmed the SGLT5 up-regulation. Our findings may indicate that the high-fructose diet increased sodium reabsorption principally through up-regulated SGLT5, finally causing salt-sensitive hypertension.

scholarly journals Regulation of the epithelial sodium channel by accessory proteins

2003 ◽  
Vol 371 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Kelly GORMLEY ◽  
Yanbin DONG ◽  
Giuseppe A. SAGNELLA
Keyword(s):  
Blood Pressure ◽  
Cystic Fibrosis ◽  
Sodium Channel ◽  
Sodium Transport ◽  
Genetic Disorders ◽  
Epithelial Sodium Channel ◽  
Sodium Balance ◽  
Sodium Reabsorption ◽  
Channel Activity ◽  
Cellular Mechanisms

The epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium fluxes in epithelial cells. Modulation of sodium reabsorption through the distal nephron ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium-channel activity (Liddle's syndrome and pseudohypoaldosteronism type 1), associated with contrasting effects on blood pressure. The mineralocorticoid aldosterone is a well-established modulator of sodium-channel activity. Considerable insight has now been gained into the intracellular signalling pathways linking aldosterone-mediated changes in gene transcription with changes in ion transport. Activating pathways include aldosterone-induced proteins and especially the serum- and glucocorticoid-inducible kinase (SGK) and the small G-protein, K-Ras 2A. Targeting of the ENaC for endocytosis and degradation is now emerging as a major mechanism for the down-regulation of channel activity. Several proteins acting in concert are an intrinsic part of this process but Nedd4 (neural precursor cell expressed developmentally down-regulated 4) is of central importance. Other mechanisms known to interact with ENaC and affect sodium transport include channel-activating protease 1 (CAP-1), a membrane-anchored protein, and the cystic fibrosis transmembrane regulator. The implications of research on accessory factors controlling ENaC activity are wide-ranging. Understanding cellular mechanisms controlling ENaC activity may provide a more detailed insight not only of ion-channel abnormalities in cystic fibrosis but also of the link between abnormal renal sodium transport and essential hypertension.

scholarly journals High-salt intake enhances superoxide activity in eNOS knockout mice leading to the development of salt sensitivity

2010 ◽  
Vol 299 (3) ◽  
pp. F656-F663 ◽  
Author(s):  
Libor Kopkan ◽  
Arthur Hess ◽  
Zuzana Husková ◽  
Luděk Červenka ◽  
L. Gabriel Navar ◽  
...  
Keyword(s):  
Salt Intake ◽  
Salt Sensitivity ◽  
High Salt ◽  
No Production ◽  
Wild Type ◽  
Total N ◽  
High Salt Intake ◽  
Excretion Rates ◽  
Salt Sensitive Hypertension

A deficiency in nitric oxide (NO) generation leads to salt-sensitive hypertension, but the role of increased superoxide (O2−) in such salt sensitivity has not been delineated. We examined the hypothesis that an enhancement in O2− activity induced by high-salt (HS) intake under deficient NO production contributes to the development of salt-sensitive hypertension. Endothelial NO synthase knockout (eNOS KO; total n = 64) and wild-type (WT; total n = 58) mice were given diets containing either normal (NS; 0.4%) or high-salt (HS; 4%) for 2 wk. During this period, mice were chronically treated with a O2− scavenger, tempol (400 mg/l), or an inhibitor of NADPH oxidase, apocynin (1 g/l), in drinking water or left untreated ( n = 6–8 per group). Blood pressure was measured by radiotelemetry and 24-h urine samples were collected in metabolic cages. Basal mean arterial pressure (MAP) in eNOS KO was higher (125 ± 4 vs. 106 ± 3 mmHg) compared with WT. Feeding HS diet did not alter MAP in WT but increased it in eNOS KO to 166 ± 9 mmHg. Both tempol and apocynin treatment significantly attenuated the MAP response to HS in eNOS KO (134 ± 3 and 139 ± 4 mmHg, respectively). Basal urinary 8-isoprostane excretion rates (UIsoV), a marker for endogenous O2− activity, were similar (2.8 ± 0.2 and 2.4 ± 0.3 ng/day) in both eNOS KO and WT mice. However, HS increased UIsoV more in eNOS KO than in WT (4.6 ± 0.3 vs. 3.8 ± 0.2 ng/day); these were significantly attenuated by both tempol and apocynin treatment. These data indicate that an enhancement in O2− activity contributes substantially to the development of salt-sensitive hypertension under NO-deficient conditions.

Interactions between subtotal nephrectomy and salt: effects on blood pressure and renal function in pregnant and nonpregnant ewes

2008 ◽  
Vol 294 (4) ◽  
pp. R1227-R1233 ◽  
Author(s):  
Karen J. Gibson ◽  
Amanda C. Boyce ◽  
Clare L. Thomson ◽  
Sarah Chinchen ◽  
Eugenie R. Lumbers
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Salt Intake ◽  
High Salt ◽  
Late Gestation ◽  
Plasma Creatinine ◽  
Sodium Balance ◽  
Sodium Reabsorption ◽  
High Salt Intake ◽  
In Pregnancy

The effects of high salt intake on blood pressure and renal function were studied in nine subtotally nephrectomized pregnant ewes (STNxP) and seven intact pregnant ewes (IntP) in late gestation and in eight subtotally nephrectomized nonpregnant ewes (STNxNP) and seven intact nonpregnant ewes (IntNP). STNxP had higher mean arterial pressures ( P < 0.02) and plasma creatinine levels ( P < 0.001) than IntP. High salt (0.17 M NaCl as drinking water for 5 days) did not change blood pressure in either STNxP or IntP. STNxNP had higher mean arterial pressures ( P = 0.03) and plasma creatinine levels ( P < 0.001) than IntNP. In STNxNP, blood pressure increased with high salt intake and there was a positive relationship between diastolic pressure and sodium balance ( r = 0.497, P = 0.05). This relationship was not present in IntNP, STNxP, or IntP. Because high salt intake did not cause an increase in blood pressure in STNxP, it is concluded that they were protected by pregnancy from further rises in blood pressure. The observed increase in glomerular filtration rate ( P < 0.03) and depression of fractional proximal sodium reabsorption ( P = 0.003) that occurred in STNxP, but not in STNxNP, in response to high salt may have contributed to this protection. As well, the increased production of vasorelaxants in pregnancy may selectively protect against the occurrence of salt-sensitive hypertension in pregnancy.

Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension

2007 ◽  
Vol 293 (1) ◽  
pp. R251-R256 ◽  
Author(s):  
Martha Franco ◽  
Flavio Martínez ◽  
Yasmir Quiroz ◽  
Othir Galicia ◽  
Rocio Bautista ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Immune Cell ◽  
Salt Intake ◽  
Experimental Models ◽  
High Salt ◽  
Salt Diet ◽  
High Salt Intake ◽  
Plasma Angiotensin ◽  
Salt Sensitive Hypertension

Renal immune cell infiltration and cells expressing angiotensin II (AII) in tubulointerstitial areas of the kidney are features of experimental models of salt-sensitive hypertension (SSHTN). A high-salt intake tends to suppress circulating AII levels, but intrarenal concentrations of AII have not been investigated in SSHTN. This study explored the relationship between these features to gain insight into the pathophysiology of SSHTN. Plasma angiotensin II (AII) and renal interstitial AII (microdialysis technique) and the infiltration of macrophages, lymphocytes, and AII-positive cells were determined in SSHTN induced by 5 wk of a high-salt diet (HSD) after short-term infusion of AII in rats with ( n = 10) and without ( n = 11) treatment with mycophenolate mofetil (MMF) and in control rats fed a high- ( n = 7) and normal ( n = 11) salt diet. As in previous studies, MMF did not affect AII-associated hypertension but reduced the interstitial inflammation and the SSHTN in the post-AII-period. During the HSD period, the AII group untreated with MMF had mean ± SD) low plasma (2.4 ± 1.4 pg/ml) and high interstitial AII concentration (1,310 ± 208 pg/ml); MMF treatment resulted in a significantly lower interstitial AII (454 ± 128 pg/ml). Renal AII concentration and the number of tubulointerstitial AII-positive cells were correlated. Blood pressure correlated positively with interstitial AII and negatively with plasma AII, thus giving compelling evidence of the paramount role of the AII within the kidney in the AII-induced model of salt-driven hypertension.

Role of Vasopressin in Blood Pressure Control of Spontaneously Hypertensive Rats

1978 ◽  
Vol 55 (s4) ◽  
pp. 247s-250s ◽  
Author(s):  
Jan Möhring ◽  
Jacqueline Kintz ◽  
Josiane Schoun
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Control ◽  
Spontaneously Hypertensive Rats ◽  
Salt Intake ◽  
Renin Angiotensin System ◽  
Pressure Control ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
High Salt Intake

1. The role of arginine—vasopressin (AVP) and of angiotensin in blood pressure control of spontaneously hypertensive rats (SH rats, stroke-prone strain) was studied. 2. In SH rats, which drank water or 1% NaCl, plasma AVP concentrations were elevated during the benign course of hypertension and increased further when the animals entered the malignant phase. Blood pressure correlated significantly with plasma AVP concentrations in SH rats on water, but not in SH rats on saline. 3. The injection of a specific AVP antiserum lowered blood pressure significantly in SH rats on water and in SH rats on saline. 4. When the correlation between blood pressure and plasma AVP of SH rats on water was compared with the respective correlation obtained during infusion of AVP into normotensive rats, a marked shift to the left became apparent, the factor of displacement amounting to more than 1000. 5. Saralasin did not affect blood pressure of SH rats on water, except for two rats with malignant hypertension. However, in SH rats on saline, saralasin lowered blood pressure significantly. 6. It is concluded that in SH rats AVP plays an important vasopressor role in blood pressure control and that sensitization to the vasopressor effect of AVP occurs in these animals. The renin—angiotensin system is significantly involved in blood pressure control of SH rats only when they are subjected to high salt intake.

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