ArticleJournal of the American Society of Nephrology : JASN2015
The Effect of WNK4 on the Na+-Cl- Cotransporter Is Modulated by Intracellular Chloride.
Article in Journal of the American Society of Nephrology : JASN, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers.
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Who cites it
103 citing papers in PubMed, 153 citations in OpenAlex.
- The kidney distal tubule potassium switch, modern diet and hypertension.Nature reviews. Nephrology · 2026Review
- Exploring the Role of the SLC12A Cation-Coupled Chloride Cotransporters in the Cardiovascular System.Cells · 2026Review
- Association of Serum Chloride Concentration With All-Cause and Cardiovascular Mortality in Patients Undergoing Peritoneal Dialysis: The Fukuoka Peritoneal Dialysis Registry.Kidney medicine · 2026Article
- Chloride at the spotlight-but not alone: towards a multi-ionic diuretic strategy.Clinical kidney journal · 2026Review
- Article
- Hypochloremia is an underutilised prognostic marker in patients with advanced liver cirrhosis and liver failure.World journal of hepatology · 2025Review
- The evolving concepts of KS-WNK1 effect on NCC activity.American journal of physiology. Renal physiology · 2025Review
- Familial Hyperkalemic Hypertension.Comprehensive Physiology · 2024Review
- Inverse association between serum chloride levels and the risk of atrial fibrillation in chronic kidney disease patients.Clinical kidney journal · 2024Article
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Association between serum chloride and in-hospital mortality in congestive heart failure with diabetes: Data from the MIMIC-IV database.Journal of diabetes and metabolic disorders · 2024Article
- Effect of low sodium and high potassium diet on lowering blood pressure and cardiovascular events.Clinical hypertension · 2024Review
- Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1α-mediated mitochondrial homeostasis in diabetic kidney disease.Cellular and molecular life sciences : CMLS · 2023Article
- Expression of the kidney anion exchanger 1 affects WNK4 and SPAK phosphorylation and results in claudin-4 phosphorylation.Heliyon · 2023Article
- Dietary potassium stimulates Ppp1Ca-Ppp1r1a dephosphorylation of kidney NaCl cotransporter and reduces blood pressure.The Journal of clinical investigation · 2023Article
- Thirty years of the NaCl cotransporter: from cloning to physiology and structure.American journal of physiology. Renal physiology · 2023Review
- Cullin 3 and Blood Pressure Regulation: Insights From Familial Hyperkalemic Hypertension.Hypertension (Dallas, Tex. : 1979) · 2023Review
- Consideration of Kinase Inhibitors for the Treatment of Hydrocephalus.International journal of molecular sciences · 2023Review
- Review
- The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter.Frontiers in physiology · 2023Review
43 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 3 countries.
Funding
Abstract
It is widely recognized that the phenotype of familial hyperkalemic hypertension is mainly a consequence of increased activity of the renal Na(+)-Cl(-) cotransporter (NCC) because of altered regulation by with no-lysine-kinase 1 (WNK1) or WNK4. The effect of WNK4 on NCC, however, has been controversial because both inhibition and activation have been reported. It has been recently shown that the long isoform of WNK1 (L-WNK1) is a chloride-sensitive kinase activated by a low Cl(-) concentration. Therefore, we hypothesized that WNK4 effects on NCC could be modulated by intracellular chloride concentration ([Cl(-)]i), and we tested this hypothesis in oocytes injected with NCC cRNA with or without WNK4 cRNA. At baseline in oocytes, [Cl(-)]i was near 50 mM, autophosphorylation of WNK4 was undetectable, and NCC activity was either decreased or unaffected by WNK4. A reduction of [Cl(-)]i, either by low chloride hypotonic stress or coinjection of oocytes with the solute carrier family 26 (anion exchanger)-member 9 (SLC26A9) cRNA, promoted WNK4 autophosphorylation and increased NCC-dependent Na(+) transport in a WNK4-dependent manner. Substitution of the leucine with phenylalanine at residue 322 of WNK4, homologous to the chloride-binding pocket in L-WNK1, converted WNK4 into a constitutively autophosphorylated kinase that activated NCC, even without chloride depletion. Elimination of the catalytic activity (D321A or D321K-K186D) or the autophosphorylation site (S335A) in mutant WNK4-L322F abrogated the positive effect on NCC. These observations suggest that WNK4 can exert differential effects on NCC, depending on the intracellular chloride concentration.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.