ArticleThe Journal of clinical investigation2003
WNK kinases regulate thiazide-sensitive Na-Cl cotransport.
Article in The Journal of clinical investigation, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 185 papers.
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Who cites it
185 citing papers in PubMed, 437 citations in OpenAlex.
- No lysine? No problem: the surprising roles of WNK kinases in physiology and disease.The Biochemical journal · 2026Review
- Pathophysiological Mechanisms and Clinical Controversies of Sodium-Induced Hypertension: A Multi-Systemic Perspective.Nutrients · 2026Review
- Use of acetazolamide in volume overload: start at the beginning.Clinical kidney journal · 2026Review
- Central Osmolality Sensing for Arginine Vasopressin Release Is Mediated by WNK1-OSR1/SPAK-Kv3.1 Cascade.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Activation of WNK1 signaling through Piezo1.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth.Nature communications · 2025Article
- The evolving concepts of KS-WNK1 effect on NCC activity.American journal of physiology. Renal physiology · 2025Review
- Familial Hyperkalemic Hypertension.Comprehensive Physiology · 2024Review
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Monogenic Hypertension Linked to the Renin-Angiotensin-Aldosterone System.Anatolian journal of cardiology · 2024Article
- KDM6A Demethylase Regulates Renal Sodium Excretion and Blood Pressure.Hypertension (Dallas, Tex. : 1979) · 2024Article
- Expression of the kidney anion exchanger 1 affects WNK4 and SPAK phosphorylation and results in claudin-4 phosphorylation.Heliyon · 2023Article
- Thirty years of the NaCl cotransporter: from cloning to physiology and structure.American journal of physiology. Renal physiology · 2023Review
- Serum Chloride and Heart Failure.Kidney medicine · 2023Review
- Aldosterone: Renal Action and Physiological Effects.Comprehensive Physiology · 2023Article
- Review
- Kidney ion handling genes and their interaction in blood pressure control.Bioscience reports · 2022Review
- Potassium Homeostasis and WNK Kinases in the Regulation of the Sodium-Chloride Cotransporter: Hyperaldosteronism and Its Metabolic Consequences.Kidney360 · 2022Article
- A narrative review of Hyporeninemic hypertension-an indicator for monogenic forms of hypertension.Pediatric medicine (Hong Kong, China) · 2022Article
- How Many Cell Types Are in the Kidney and What Do They Do?Annual review of physiology · 2022Review
125 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Pseudohypoaldosteronism type II (PHAII) is an autosomal dominant disorder of hyperkalemia and hypertension. Mutations in two members of the WNK kinase family, WNK1 and WNK4, cause the disease. WNK1 mutations are believed to increase WNK1 expression; the effect of WNK4 mutations remains unknown. The clinical phenotype of PHAII is opposite to Gitelman syndrome, a disease caused by dysfunction of the thiazide-sensitive Na-Cl cotransporter. We tested the hypothesis that WNK kinases regulate the mammalian thiazide-sensitive Na-Cl cotransporter (NCC). Mouse WNK4 was cloned and expressed in Xenopus oocytes with or without NCC. Coexpression with WNK4 suppressed NCC activity by more than 85%. This effect did not result from defects in NCC synthesis or processing, but was associated with an 85% reduction in NCC abundance at the plasma membrane. Unlike WNK4, WNK1 did not affect NCC activity directly. WNK1, however, completely prevented WNK4 inhibition of NCC. Some WNK4 mutations that cause PHAII retained NCC-inhibiting activity, but the Q562E WNK4 demonstrated diminished activity, suggesting that some PHAII mutations lead to loss of NCC inhibition. Gain-of-function WNK1 mutations would be expected to inhibit WNK4 activity, thereby activating NCC, contributing to the PHAII phenotype. Together, these results identify WNK kinases as a previously unrecognized sodium regulatory pathway of the distal nephron. This pathway likely contributes to normal and pathological blood pressure homeostasis.
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Registered trials
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.