ArticleThe Journal of clinical investigation2007
The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.
Article in The Journal of clinical investigation, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 130 citations in OpenAlex.
- Machine learning models predict mortality risk in diabetic neuropathy patients using MIMIC-IV data.Scientific reports · 2025Article
- Kidney-specific WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates.The Journal of clinical investigation · 2025Article
- The evolving concepts of KS-WNK1 effect on NCC activity.American journal of physiology. Renal physiology · 2025Review
- 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
- Molecular Mechanisms of Na-Cl Cotransporter in Relation to Hypertension in Chronic Kidney Disease.International journal of molecular sciences · 2022Review
- Kidney ion handling genes and their interaction in blood pressure control.Bioscience reports · 2022Review
- Soluble (Pro)Renin Receptor as a Negative Regulator of NCC (NaHypertension (Dallas, Tex. : 1979) · 2021Article
- WNK4 kinase: from structure to physiology.American journal of physiology. Renal physiology · 2021Review
- A novel homozygous mutation (p.N958K) of SLC12A3 in Gitelman syndrome is associated with endoplasmic reticulum stress.Journal of endocrinological investigation · 2021Article
- Hypochloraemia in Patients with Heart Failure: Causes and Consequences.Cardiology and therapy · 2020Review
- Hereditary causes of primary aldosteronism and other disorders of apparent excess mineralocorticoid activity.Gland surgery · 2020Review
- Relationship between a Weighted Multi-Gene Algorithm and Blood Pressure Control in Hypertension.Journal of clinical medicine · 2019Article
- The Effect of Genetically Guided Mathematical Prediction and the Blood Pressure Response to Pharmacotherapy in Hypertension Patients.Clinical Medicine Insights. Cardiology · 2019Article
- GABANature communications · 2017Article
- CD8Nature communications · 2017Article
- NaCl cotransporter abundance in urinary vesicles is increased by calcineurin inhibitors and predicts thiazide sensitivity.PloS one · 2017Article
- Potassium and Its Discontents: New Insight, New Treatments.Journal of the American Society of Nephrology : JASN · 2016Review
- Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis.Kidney international · 2016Article
17 more citing papers are in PubMed but not listed here.
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3 authors at 2 institutions in 1 country.
Funding
Abstract
The pathogenesis of essential hypertension remains unknown, but thiazide diuretics are frequently recommended as first-line treatment. Recently, familial hyperkalemic hypertension (FHHt) was shown to result from activation of the thiazide-sensitive Na-Cl cotransporter (NCC) by mutations in WNK4, although the mechanism for this effect remains unknown. WNK kinases are unique members of the human kinome, intimately involved in maintaining electrolyte balance across cell membranes and epithelia. Previous work showed that WNK1, WNK4, and a kidney-specific isoform of WNK1 interact to regulate NCC activity, suggesting that WNK kinases form a signaling complex. Here, we report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes, further supporting the WNK signaling complex hypothesis. We demonstrate that physiological regulation of NCC in oocytes results from antagonism between WNK3 and WNK4 and that FHHt-causing WNK4 mutations exert a dominant-negative effect on wild-type (WT) WNK4 to mimic a state of WNK3 excess. The results provide a mechanistic explanation for the divergent effects of WT and FHHt-mutant WNK4 on NCC activity, and for the dominant nature of FHHt in humans and genetically modified mice.
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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.