Sodium Chloride Cotransporter Upregulation in Settings of Zinc Deficiency Offers New Insight into Blood Pressure Dysregulation in Chronic Diseases

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.

Download Full-text

Heterozygous mutations of the sodium chloride cotransporter in Chinese children: prevalence and association with blood pressure

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfn619 ◽

2008 ◽

Vol 24 (4) ◽

pp. 1170-1175 ◽

Cited By ~ 9

Author(s):

Y.-J. Hsu ◽

S.-S. Yang ◽

N.-F. Chu ◽

H.-K. Sytwu ◽

C.-J. Cheng ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Chloride ◽

Chinese Children ◽

Sodium Chloride Cotransporter

Download Full-text

Role of ClC-K and barttin in low potassium-induced sodium chloride cotransporter activation and hypertension in mouse kidney

Bioscience Reports ◽

10.1042/bsr20171243 ◽

2018 ◽

Vol 38 (1) ◽

Cited By ~ 9

Author(s):

Naohiro Nomura ◽

Wakana Shoda ◽

Yuanlong Wang ◽

Shintaro Mandai ◽

Taisuke Furusho ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Chloride ◽

Ex Vivo ◽

Extracellular Potassium ◽

Sodium Chloride Cotransporter ◽

Low Potassium ◽

Wnk Kinases

The sodium chloride cotransporter (NCC) has been identified as a key molecule regulating potassium balance. The mechanisms of NCC regulation during low extracellular potassium concentrations have been studied in vitro. These studies have shown that hyperpolarization increased chloride efflux, leading to the activation of chloride-sensitive with-no-lysine kinase (WNK) kinases and their downstream molecules, including STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NCC. However, this mechanism was not studied in vivo. Previously, we developed the barttin hypomorphic mouse (Bsndneo/neo mice), expressing very low levels of barttin and ClC-K channels, because barttin is an essential β-subunit of ClC-K. In contrast with Bsnd−/− mice, Bsndneo/neo mice survived to adulthood. In Bsndneo/neo mice, SPAK and NCC activation after consuming a low-potassium diet was clearly impaired compared with that in wild-type (WT) mice. In ex vivo kidney slice experiment, the increase in pNCC and SPAK in low-potassium medium was also impaired in Bsndneo/neo mice. Furthermore, increased blood pressure was observed in WT mice fed a high-salt and low-potassium diet, which was not evident in Bsndneo/neo mice. Thus, our study provides in vivo evidence that, in response to a low-potassium diet, ClC-K and barttin play important roles in the activation of the WNK4-SPAK-NCC cascade and blood pressure regulation.

Download Full-text

NFkB Mediates Renal Sodium Retention via the Sodium Chloride Cotransporter in Zinc Deficiency‐induced Hypertension

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.01833 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Cindellynn Murta ◽

Dylan Schindele ◽

Tara-Yesomi Wenegieme ◽

Aston Waite ◽

Meagan Naraine ◽

...

Keyword(s):

Sodium Chloride ◽

Zinc Deficiency ◽

Sodium Retention ◽

Sodium Chloride Cotransporter ◽

Induced Hypertension

Download Full-text

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

Hypertension ◽

10.1161/hypertensionaha.120.15928 ◽

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.

Download Full-text

NFkB Mediates Renal Sodium Retention via the Sodium Chloride Cotransporter in Zinc Deficiency‐Induced Hypertension

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.02972 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Cindellynn Murta ◽

Dylan Schindele ◽

Meagan Naraine ◽

Tara‐Yesomi Wenegieme ◽

Aston Waite ◽

...

Keyword(s):

Sodium Chloride ◽

Zinc Deficiency ◽

Sodium Retention ◽

Sodium Chloride Cotransporter ◽

Induced Hypertension

Download Full-text

The sodium chloride cotransporter (NCC) and epithelial sodium channel (ENaC) associate

Biochemical Journal ◽

10.1042/bcj20160312 ◽

2016 ◽

Vol 473 (19) ◽

pp. 3237-3252 ◽

Cited By ~ 22

Author(s):

Abinash C. Mistry ◽

Brandi M. Wynne ◽

Ling Yu ◽

Viktor Tomilin ◽

Qiang Yue ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Chloride ◽

Sodium Channel ◽

Epithelial Sodium Channel ◽

Transport Proteins ◽

Salt Transport ◽

Native Page ◽

Sodium Chloride Cotransporter ◽

Direct Binding ◽

Epithelial Sodium Channel Enac

The thiazide-sensitive sodium chloride cotransporter (NCC) and the epithelial sodium channel (ENaC) are two of the most important determinants of salt balance and thus systemic blood pressure. Abnormalities in either result in profound changes in blood pressure. There is one segment of the nephron where these two sodium transporters are coexpressed, the second part of the distal convoluted tubule. This is a key part of the aldosterone-sensitive distal nephron, the final regulator of salt handling in the kidney. Aldosterone is the key hormonal regulator for both of these proteins. Despite these shared regulators and coexpression in a key nephron segment, associations between these proteins have not been investigated. After confirming apical localization of these proteins, we demonstrated the presence of functional transport proteins and native association by blue native PAGE. Extensive coimmunoprecipitation experiments demonstrated a consistent interaction of NCC with α- and γ-ENaC. Mammalian two-hybrid studies demonstrated direct binding of NCC to ENaC subunits. Fluorescence resonance energy transfer and immunogold EM studies confirmed that these transport proteins are within appropriate proximity for direct binding. Additionally, we demonstrate that there are functional consequences of this interaction, with inhibition of NCC affecting the function of ENaC. This novel finding of an association between ENaC and NCC could alter our understanding of salt transport in the distal tubule.

Download Full-text