ArticleProceedings of the National Academy of Sciences of the United States of America2014
Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 99 citations in OpenAlex.
- The kidney distal tubule potassium switch, modern diet and hypertension.Nature reviews. Nephrology · 2026Review
- Piezo1 dictates KProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Critical role of the β isoform of protein kinase C (PKCβ) in angiotensin II-induced oxidative stress in vascular smooth muscle cells.Physiological reports · 2025Article
- Article
- The evolving concepts of KS-WNK1 effect on NCC activity.American journal of physiology. Renal physiology · 2025Review
- Familial Hyperkalemic Hypertension.Comprehensive Physiology · 2024Review
- Sodium Chloride Cotransporter in Hypertension.Biomedicines · 2024Review
- Angiotensin II-Type-1a Receptor and Renal K + Wasting during Overnight Low-Na + Intake.Journal of the American Society of Nephrology : JASN · 2024Article
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Golgi dispersal in cancer stem cells promotes chemoresistance of colorectal cancer via the Golgi stress response.Cell death & disease · 2024Article
- Role of Angiotensin II Type 1a Receptor (AT1aR) of Renal Tubules in Regulating Inwardly Rectifying Potassium Channels 4.2 (Kir4.2), Kir4.1, and Epithelial NaHypertension (Dallas, Tex. : 1979) · 2024Article
- Insights into the diverse mechanisms and effects of variant CUL3-induced familial hyperkalemic hypertension.Cell communication and signaling : CCS · 2023Review
- Thirty years of the NaCl cotransporter: from cloning to physiology and structure.American journal of physiology. Renal physiology · 2023Review
- Mineralocorticoid Receptor Antagonists for Preventing Chronic Kidney Disease Progression: Current Evidence and Future Challenges.International journal of molecular sciences · 2023Review
- Aldosterone: Renal Action and Physiological Effects.Comprehensive Physiology · 2023Article
- Advances in the potential roles of Cullin-RING ligases in regulating autoimmune diseases.Frontiers in immunology · 2023Review
- Control of sodium and potassium homeostasis by renal distal convoluted tubules.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2023Article
- The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter.Frontiers in physiology · 2023Review
- Blood pressure effects of sodium transport along the distal nephron.Kidney international · 2022Review
- Multiple molecular mechanisms are involved in the activation of the kidney sodium-chloride cotransporter by hypokalemia.Kidney international · 2022Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
Abstract
Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K(+) reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K(+) secretion. Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)--components of an E3 ubiquitin ligase complex that targets WNKs for degradation--cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. The normal mechanisms that regulate the activity of this ubiquitin ligase and levels of WNKs have been unknown. We posited that missense mutations in KLHL3 that impair binding of WNK4 might represent a phenocopy of the normal physiologic response to volume depletion in which salt reabsorption is maximized. We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. This phosphorylation can be induced by angiotensin II (AII) signaling. Consistent with these in vitro observations, AII administration to mice, even in the absence of volume depletion, induces renal KLHL3(S433) phosphorylation and increased levels of both WNK4 and the NaCl cotransporter. Thus, AII, which is selectively induced in volume depletion, provides the signal that prevents CUL3/KLHL3-mediated degradation of WNK4, directing the kidney to maximize renal salt reabsorption while inhibiting K(+) secretion in the setting of volume depletion.
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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.