ArticleProceedings of the National Academy of Sciences of the United States of America2012
Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 160 papers.
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Who cites it
160 citing papers in PubMed, 256 citations in OpenAlex.
- The kidney distal tubule potassium switch, modern diet and hypertension.Nature reviews. Nephrology · 2026Review
- Molecular Basis of Rare Inherited Tubulopathies of the Kidney: A Primer for Clinicians.International journal of molecular sciences · 2026Review
- Long-acting RNAi therapeutics in hypertension: limitations of single-target AGT silencing and rational multi-target synergistic strategies.Frontiers in pharmacology · 2026Review
- The functional study of novel KLHL3 missense mutations associated with pseudohypoaldosteronism type II.Endocrine · 2025Article
- Effects of proximal tubule-specific ATRAP enhancement on hypertension in a remnant kidney chronic kidney disease model of mice.Scientific reports · 2025Article
- NRBP1 and TSC22D proteins affect distal convoluted tubule physiology through modulation of the WNK pathway.Science advances · 2025Article
- The evolving concepts of KS-WNK1 effect on NCC activity.American journal of physiology. Renal physiology · 2025Review
- Peroxiredoxin 5 Acts as a Negative Regulator of the Sodium-Chloride Cotransporter Involved in Alleviating Angiotensin II-Induced Hypertension.Antioxidants (Basel, Switzerland) · 2025Article
- Familial Hyperkalemic Hypertension.Comprehensive Physiology · 2024Review
- NRBP1 and TSC22D proteins impact distal convoluted tubule physiology through modulation of the WNK pathway.bioRxiv : the preprint server for biology · 2024Article
- Role of calcineurin in regulating renal potassium (KActa physiologica (Oxford, England) · 2024Review
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.Nature communications · 2024Article
- Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC.Hypertension (Dallas, Tex. : 1979) · 2024Article
- Current perspective on circadian function of the kidney.American journal of physiology. Renal physiology · 2024Review
- Arginine vasopressin regulates the renal NaAmerican journal of physiology. Renal physiology · 2024Article
- Update on NKCC2 regulation in the thick ascending limb (TAL) by membrane trafficking, phosphorylation, and protein-protein interactions.Frontiers in physiology · 2024Review
- Dysregulation of the WNK4-SPAK/OSR1 pathway has a minor effect on baseline NKCC2 phosphorylation.American journal of physiology. Renal physiology · 2024Article
- The role ofJournal of pharmaceutical analysis · 2023Review
- Insights into the diverse mechanisms and effects of variant CUL3-induced familial hyperkalemic hypertension.Cell communication and signaling : CCS · 2023Review
100 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 4 countries.
Funding
Abstract
Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations in the with-no-lysine kinase 4 (WNK4). Several studies have shown that WNK4 modulates the activity of the renal Na(+)Cl(-) cotransporter, NCC. Because the renal consequences of WNK4 carrying pseudoaldosteronism type II mutations resemble the response to intravascular volume depletion (promotion of salt reabsorption without K(+) secretion), a condition that is associated with high angiotensin II (AngII) levels, it has been proposed that AngII signaling might affect WNK4 modulation of the NCC. In Xenopus laevis oocytes, WNK4 is required for modulation of NCC activity by AngII. To demonstrate that WNK4 is required in the AngII-mediated regulation of NCC in vivo, we used a total WNK4-knockout mouse strain (WNK4(-/-)). WNK4 mRNA and protein expression were absent in WNK4(-/-) mice, which exhibited a mild Gitelman-like syndrome, with normal blood pressure, increased plasma renin activity, and reduced NCC expression and phosphorylation at T-58. Immunohistochemistry revealed normal morphology of the distal convoluted tubule with reduced NCC expression. Low-salt diet or infusion of AngII for 4 d induced phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and of NCC at S-383 and T-58, respectively, in WNK4(+/+) but not WNK4(-/-) mice. Thus, the absence of WNK4 in vivo precludes NCC and SPAK phosphorylation promoted by a low-salt diet or AngII infusion, suggesting that AngII action on the NCC occurs via a WNK4-SPAK-dependent signaling pathway. Additionally, stimulation of aldosterone secretion by AngII, but not by a high-K(+) diet, was impaired in WNK4(-/-) 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.