scholarly journals Impaired Regulation of the Renal Sodium Chloride Cotransporter (NCC) in Animal Models of Salt‐Sensitive Hypertension

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Kathryn Walsh ◽  
Richard Wainford
Keyword(s):  
Sodium Chloride ◽  
Animal Models ◽  
Sodium Chloride Cotransporter ◽  
Salt Sensitive Hypertension

scholarly journals Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats

2016 ◽  
Vol 310 (2) ◽  
pp. R115-R124 ◽  
Author(s):  
Kathryn R. Walsh ◽  
Jill T. Kuwabara ◽  
Joon W. Shim ◽  
Richard D. Wainford
Keyword(s):  
Blood Pressure ◽  
Sodium Chloride ◽  
Salt Sensitivity ◽  
Dietary Sodium ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sodium Chloride Cotransporter ◽  
Sprague Dawley Rats ◽  
Salt Sensitive Hypertension ◽  
The Impact

Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (μeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development 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.

Abstract 076: Urinary Exosomal Epithelial Sodium Channel And Sodium-chloride Cotransporter Measurement In Humans

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
TAOPHEEQ A MUSTAPHA ◽  
VICTOR NWAZUE ◽  
KEVIN SCHEY ◽  
RAJ SATISH ◽  
JAMES M LUTHER
Keyword(s):  
Sodium Chloride ◽  
Sodium Channel ◽  
Multiple Reaction Monitoring ◽  
Epithelial Sodium Channel ◽  
Sodium Balance ◽  
Sodium Reabsorption ◽  
Dependent Manner ◽  
Creatinine Concentration ◽  
Spot Urine ◽  
Sodium Chloride Cotransporter

Sodium reabsorption in the distal nephron is tightly regulated in part by epithelial sodium channel (ENaC) and sodium chloride cotransporter (NCC), although non-invasive measure of these proteins in humans has not previously been feasible. We recently analyzed the urinary exosomal proteome and identified candidate targets for quantification of ENaC and NCC using targeted mass spectrometry. To test the hypothesis that urinary exosomal ENaC and NCC are altered during renin-angiotensin-aldosterone system activation, we activated the endogenous RAAS using a low sodium diet (LS) in two separate studies. We provided 8 subjects LS diet (10mmol/day for 7days) to assess urinary protein excretion at 7 days (study 1) and longitudinally over the course of 1 week (study 2). Daily 24-hour urine was collected to monitor sodium balance, and spot urine samples were obtained each morning on days 0, 2, 4, and 6 of LS diet. Urinary exosomal ENaC-α, ENaC-γ, and NCC peptides were analyzed using targeted multiple-reaction-monitoring analysis quantified with stable-isotope peptide standards, and results were normalized to urine creatinine concentration. In study 1, urinary ENaCγ increased after 8 days of LS diet (Figure A). In study 2, urinary exosomal ENaCγ (Figure B) and NCC peptides (Figure C) increased in a time-dependent manner during LS diet. These measures of urinary sodium channel expression may provide further insight into distal sodium reabsorption in human hypertension.

scholarly journals Characterization of a novel phosphorylation site in the sodium-chloride cotransporter, NCC

2012 ◽  
Vol 590 (23) ◽  
pp. 6121-6139 ◽  
Author(s):  
L. L. Rosenbaek ◽  
M. Assentoft ◽  
N. B. Pedersen ◽  
N. MacAulay ◽  
R. A. Fenton
Keyword(s):  
Sodium Chloride ◽  
Phosphorylation Site ◽  
Sodium Chloride Cotransporter

Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension

2008 ◽  
Vol 295 (2) ◽  
pp. F556-F567 ◽  
Author(s):  
Giovambattista Capasso ◽  
Maria Rizzo ◽  
Maria Lisa Garavaglia ◽  
Francesco Trepiccione ◽  
Miriam Zacchia ◽  
...  
Keyword(s):  
Chloride Channels ◽  
Renal Cortex ◽  
Outer Medulla ◽  
Western Blots ◽  
Sodium Chloride Cotransporter ◽  
Normotensive Strain ◽  
Active Channels ◽  
Salt Sensitive Hypertension ◽  
Convoluted Tubules

We investigated which of the NaCl transporters are involved in the maintenance of salt-sensitive hypertension. Milan hypertensive (MHS) rats were studied 3 mo after birth. In MHS, compared with normotensive strain (MNS), mRNA abundance, quantified by competitive PCR on isolated tubules, was unchanged, both for Na+/H+ isoform 3 (NHE3) and Na+-K+-2Cl− (NKCC2), but higher (119%, n = 5, P < 0.005) for Na+-Cl− (NCC) in distal convoluted tubules (DCT). These results were confirmed by Western blots, which revealed: 1) unchanged NHE3 in the cortex and NKCC2 in the outer medulla; 2) a significant increase (52%, n = 6, P < 0.001) of NCC in the cortex; 3) α- and β-sodium channels [epithelial Na+ channel (ENaC)] unaffected in renal cortex and slightly reduced in the outer medulla, while γ-ENaC remained unchanged. Pendrin protein expression was unaffected. The role of NCC was reinforced by immunocytochemical studies showing increased NCC on the apical membrane of DCT cells of MHS animals, and by clearance experiments demonstrating a larger sensitivity ( P < 0.001) to bendroflumethiazide in MHS rats. Kidney-specific chloride channels (ClC-K) were studied by Western blot experiments on renal cortex and by patch-clamp studies on primary culture of DCT dissected from MNS and MHS animals. Electrophysiological characteristics of ClC-K channels were unchanged in MHS rats, but the number of active channels in a patch was 0.60 ± 0.21 ( n = 35) in MNS rats and 2.17 ± 0.59 ( n = 23) in MHS rats ( P < 0.05). The data indicate that, in salt-sensitive hypertension, there is a strong upregulation, both of NCC and ClC-K along the DCT, which explains the persistence of hypertension.

scholarly journals Paradoxical activation of the sodium chloride cotransporter (NCC) without hypertension in kidney deficient in a regulatory subunit of Na,K-ATPase, FXYD2

2014 ◽  
Vol 2 (12) ◽  
pp. e12226 ◽  
Author(s):  
Elena Arystarkhova ◽  
Donna L. Ralph ◽  
Yi Bessie Liu ◽  
Richard Bouley ◽  
Alicia A. McDonough ◽  
...  
Keyword(s):  
Sodium Chloride ◽  
Regulatory Subunit ◽  
Sodium Chloride Cotransporter
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