ArticleProceedings of the National Academy of Sciences of the United States of America2011
Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension.Nature genetics · 2016Pooled it
- No lysine? No problem: the surprising roles of WNK kinases in physiology and disease.The Biochemical journal · 2026Review
- Physiological functions and pharmacological targeting of transient receptor potential channels.Pharmacological reviews · 2025Review
- Article
- Familial Hyperkalemic Hypertension.Comprehensive Physiology · 2024Review
- The role and mechanism of vascular wall cell ion channels in vascular fibrosis remodeling.Channels (Austin, Tex.) · 2024Review
- Involvement of transient receptor potential channels in ocular diseases: a narrative review.Annals of translational medicine · 2022Article
- Percutaneous Delivery of Antihypertensive Agents: Advances and Challenges.AAPS PharmSciTech · 2020Review
- Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension.JCI insight · 2019Article
- Transient Receptor Potential Canonical 3 and Nuclear Factor of Activated T Cells C3 Signaling Pathway Critically Regulates Myocardial Fibrosis.Antioxidants & redox signaling · 2019Article
- Overexpression of WNK1 in POMC-expressing neurons reduces weigh gain via WNK4-mediated degradation of Kir6.2.Molecular and cellular biochemistry · 2018Article
- Enhanced Mitochondrial Transient Receptor Potential Channel, Canonical Type 3-Mediated Calcium Handling in the Vasculature From Hypertensive Rats.Journal of the American Heart Association · 2017Article
- Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles.Comprehensive Physiology · 2017Review
- Resistance to pathologic cardiac hypertrophy and reduced expression of CaV1.2 in Trpc3-depleted mice.Molecular and cellular biochemistry · 2016Article
- Hypertension: the missing WNKs.American journal of physiology. Renal physiology · 2016Review
- Vasodysfunction That Involves Renal Vasodysfunction, Not Abnormally Increased Renal Retention of Sodium, Accounts for the Initiation of Salt-Induced Hypertension.Circulation · 2016Review
- Transient receptor potential channels in the vasculature.Physiological reviews · 2015Review
- Mechanism of salt-sensitive hypertension: focus on adrenal and sympathetic nervous systems.Journal of the American Society of Nephrology : JASN · 2014Review
- Chloride sensing by WNK1 involves inhibition of autophosphorylation.Science signaling · 2014Article
- Transient receptor potential (TRP) channels: a clinical perspective.British journal of pharmacology · 2014Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension. WNK4 regulates diverse ion transporters in the kidney, and dysregulation of renal transporters is considered the main cause of the WNK4 mutation-associated hypertension. Another determinant of hypertension is vascular tone that is regulated by Ca(2+)-dependent blood vessel constriction. However, the role of WNK4 in vasoconstriction as part of its function to regulate blood pressure is not known. Here, we report that WNK4 is a unique modulator of blood pressure by restricting Ca(2+) influx via the transient receptor potential canonical 3 (TRPC3) channel in the vasculature. Loss of WNK4 markedly augmented TRPC3-mediated Ca(2+) influx in vascular smooth muscle cells (VSMCs) in response to α-adrenoreceptor stimulation, which is the pathological hallmark of hypertension in resistance arteries. Notably, WNK4 depletion induced hypertrophic cell growth in VSMCs and increased vasoconstriction in small mesenteric arteries via TRPC3-mediated Ca(2+) influx. In addition, WNK4 mutants harboring the Q562E PHAII-causing or the D318A kinase-inactive mutation failed to mediate TRPC3 inhibition. These results define a previously undescribed function of WNK4 and reveal a unique therapeutic target to control blood pressure in WNK4-related hypertension.
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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.