Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis

Hoorn, Ewout J.; Gritter, Martin; Cuevas, Catherina A.; Fenton, Robert A.

doi:10.1152/physrev.00044.2018

Cited by 118 publications

(159 citation statements)

References 405 publications

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“…The Cl − regulation of WNK has been best studied in the DCT which constitutes a sensor for plasma K + (Hoorn et al, 2020). A change in plasma [K + ], through Kir4.1/1.1 channels, will lead to parallel changes in intracellular K + and Cl − concentrations in the DCT (Su et al, 2019).…”

Section: Na-cl Cotransporter (Ncc)mentioning

confidence: 99%

Sodium Transporters in Human Health and Disease

Gagnon

Delpire

2021

Front. Physiol.

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Sodium (Na+) electrochemical gradients established by Na+/K+ ATPase activity drives the transport of ions, minerals, and sugars in both excitable and non-excitable cells. Na+-dependent transporters can move these solutes in the same direction (cotransport) or in opposite directions (exchanger) across both the apical and basolateral plasma membranes of polarized epithelia. In addition to maintaining physiological homeostasis of these solutes, increases and decreases in sodium may also initiate, directly or indirectly, signaling cascades that regulate a variety of intracellular post-translational events. In this review, we will describe how the Na+/K+ ATPase maintains a Na+ gradient utilized by multiple sodium-dependent transport mechanisms to regulate glucose uptake, excitatory neurotransmitters, calcium signaling, acid-base balance, salt-wasting disorders, fluid volume, and magnesium transport. We will discuss how several Na+-dependent cotransporters and Na+-dependent exchangers have significant roles in human health and disease. Finally, we will discuss how each of these Na+-dependent transport mechanisms have either been shown or have the potential to use Na+ in a secondary role as a signaling molecule.

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Section: Na-cl Cotransporter (Ncc)mentioning

confidence: 99%

Sodium Transporters in Human Health and Disease

Gagnon

Delpire

2021

Front. Physiol.

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“…Several co-transporters and ion channels are involved in the complex regulatory reabsorption system of the 15-20% of filtered potassium in the thick ascending limb of the loop of Henle. The best characterized is the sodium potassium chloride cotransporter also known as NKCC2 (7). NKCC2 has one of the highest overall reabsorptive capacities in the kidney.…”

Section: Classic Feedback Regulation and Feedforward Control: Two Mechanisms Of Potassium Regulationmentioning

confidence: 99%

Management of Chronic Hyperkalemia in Patients With Chronic Kidney Disease: An Old Problem With News Options

2021

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Hyperkalemia is one of the main electrolyte disorders in patients with chronic kidney disease (CKD). The prevalence of hyperkalemia increases as the Glomerular Filtration Rate (GFR) declines. Although chronic hyperkalemia is not a medical emergency, it can have negative consequences for the adequate cardio-renal management in the medium and long term. Hyperkalemia is common in patients on renin-angiotensin-aldosterone system inhibitors (RAASi) or Mineralocorticoid Receptor Antagonists (MRAs) and can affect treatment optimization for hypertension, diabetes mellitus, heart failure (HF), and CKD. Mortality rates are higher with suboptimal dosing among patients with CKD, diabetes or HF compared with full RAASi dosing, and are the highest among patients who discontinue RAASis. The treatment of chronic hyperkalemia is still challenging. Therefore, in the real world, discontinuation or reduction of RAASi therapy may lead to adverse cardiorenal outcomes, and current guidelines differ with regard to recommendations on RAASi therapy to enhance cardio and reno-protective effects. Treatment options for hyperkalemia have not changed much since the introduction of the cation exchange resin over 50 years ago. Nowadays, two new potassium binders, Patiromer Sorbitex Calcium, and Sodium Zirconium Cyclosilicate (SZC) already approved by FDA and by the European Medicines Agency, have demonstrated their clinical efficacy in reducing serum potassium with a good safety profile. The use of the newer potassium binders may allow continuing and optimizing RAASi therapy in patients with hyperkalemia keeping the cardio-renal protective effect in patients with CKD and cardiovascular disease. However, further research is needed to address some questions related to potassium disorders (definition of chronic hyperkalemia, monitoring strategies, prediction score for hyperkalemia or length for treatment).

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“…Given the importance of NCC in blood pressure regulation [2], we performed telemetric blood pressure measurements in KS-WNK1-KO mice. These studies were focused on females, since they exhibited more pronounced hypokalemia and hypernatremia than males (Fig 4), and thus would be more likely to manifest detectable blood pressure differences.…”

Section: Resultsmentioning

confidence: 99%

“…Hypokalemia-mediated NCC activation limits downstream sodium transport in the connecting tubule and collecting duct, diminishing distal voltage-dependent potassium secretion. This minimizes urinary potassium losses to conserve total body K+ [2]. In contrast, hyperkalemia inhibits NCC, facilitating kaliuresis [3].…”

Section: Introductionmentioning

confidence: 99%

KS-WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates

Boyd‐Shiwarski

Beacham

Griffiths

et al. 2021

Preprint

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The distal convoluted tubule (DCT) NaCl cotransporter NCC is activated by phosphorylation, a process that is potassium-regulated and dependent on With-No-Lysine (WNK) kinases. KS-WNK1, a kidney-specific WNK1 isoform lacking the kinase domain, controls WNK signaling pathway localization in the DCT. Its role in NCC regulation, however, is unresolved: while early studies proposed that KS-WNK1 functions as an NCC inhibitor, recent work suggests that it activates NCC. To evaluate the role of KS-WNK1 on potassium-dependent NCC regulation, we studied KS-WNK1-KO mice across a wide range of plasma K+ (2.0-9.0 mmol/L), induced by dietary maneuvers and diuretic challenges. Potassium-deprived KS-WNK1-KO mice exhibited low WNK-dependent NCC phosphorylation compared to littermates, indicating that KS-WNK1 activates NCC during K+ deficiency. In contrast, relative NCC phosphorylation was high in potassium-loaded KS-WNK1-KO mice, consistent with KS-WNK1-mediated NCC inhibition during hyperkalemia. An integrated analysis revealed that KS-WNK1 expands the dynamic range of NCC responsiveness to potassium, steepening the linear inverse relationship between NCC phosphorylation and plasma [K+]. The effect of KS-WNK1 deletion was strongest in potassium-restricted females, as they developed exaggerated hypokalemia and thiazide insensitivity due to low NCC activity. Taken together, these findings indicate that KS-WNK1 is a potassium-responsive signaling amplifier that converts small changes in [K+] into large effects on NCC phosphorylation. This effect predominates in females during potassium deficiency, when high NCC activity is required to maintain salt reabsorption without exacerbating K+ losses. These observations define the role of KS-WNK1 in NCC regulation, and identify a novel mechanism that contributes to sexual dimorphism in the mammalian nephron.

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Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis

Cited by 118 publications

References 405 publications

Sodium Transporters in Human Health and Disease

Sodium Transporters in Human Health and Disease

Management of Chronic Hyperkalemia in Patients With Chronic Kidney Disease: An Old Problem With News Options

KS-WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates

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