ArticleThe Journal of clinical investigation2014
Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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Who cites it
97 citing papers in PubMed, 138 citations in OpenAlex.
- A Selective Cullin 3 RING E3 Ligase Inhibitor Attenuates Hyperglycemia via Dual Insulin Sensitizing and Insulinotropic Action.Diabetes · 2026Article
- Piezo1 dictates KProceedings of the National Academy of Sciences of the United States of America · 2026Article
- The functional study of novel KLHL3 missense mutations associated with pseudohypoaldosteronism type II.Endocrine · 2025Article
- Hypomagnesaemia-associated hypokalaemia requires activation of both ENaC and ROMK.The Journal of physiology · 2025Article
- Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cullin-3 regulates the renal baroreceptor machinery that controls renin gene expression.JCI insight · 2025Article
- Role of the Renin-Angiotensin System in Blood Pressure Regulation in Smooth Muscle-Specific Cullin-3 Deficient Mice.Hypertension (Dallas, Tex. : 1979) · 2025Article
- The evolving concepts of KS-WNK1 effect on NCC activity.American journal of physiology. Renal physiology · 2025Review
- Evaluation of large language models for discovery of gene set function.Nature methods · 2025Article
- Familial Hyperkalemic Hypertension.Comprehensive Physiology · 2024Review
- Distal convoluted tubule-specific disruption of the COP9 signalosome but not its regulatory target cullin 3 causes tubular injury.American journal of physiology. Renal physiology · 2024Article
- SMURF1/2 Are Novel Regulators of WNK1 Stability.Kinases and phosphatases · 2024Article
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Regulation of the water channel aquaporin-2 by cullin E3 ubiquitin ligases.American journal of physiology. Renal physiology · 2024Article
- Dysregulation of the WNK4-SPAK/OSR1 pathway has a minor effect on baseline NKCC2 phosphorylation.American journal of physiology. Renal physiology · 2024Article
- New insights into SUMOylation and NEDDylation in fibrosis.Frontiers in pharmacology · 2024Review
- Insights into the diverse mechanisms and effects of variant CUL3-induced familial hyperkalemic hypertension.Cell communication and signaling : CCS · 2023Review
- Targeting E3 ubiquitin ligases and their adaptors as a therapeutic strategy for metabolic diseases.Experimental & molecular medicine · 2023Review
- KLHL3-dependent WNK4 degradation affected by potassium through the neddylation and autophagy pathway.BMC nephrology · 2023Article
- Cullin 3 and Blood Pressure Regulation: Insights From Familial Hyperkalemic Hypertension.Hypertension (Dallas, Tex. : 1979) · 2023Review
37 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 6 institutions in 4 countries.
Funding
Abstract
Familial hyperkalemic hypertension (FHHt) is a monogenic disease resulting from mutations in genes encoding WNK kinases, the ubiquitin scaffold protein cullin 3 (CUL3), or the substrate adaptor kelch-like 3 (KLHL3). Disease-associated CUL3 mutations abrogate WNK kinase degradation in cells, but it is not clear how mutant forms of CUL3 promote WNK stability. Here, we demonstrated that an FHHt-causing CUL3 mutant (CUL3 Δ403-459) not only retains the ability to bind and ubiquitylate WNK kinases and KLHL3 in cells, but is also more heavily neddylated and activated than WT CUL3. In cells, activated CUL3 Δ403-459 depleted KLHL3, preventing WNK degradation, despite increased CUL3-mediated WNK ubiquitylation; therefore, CUL3 loss in kidney should phenocopy FHHt in murine models. As predicted, nephron-specific deletion of Cul3 in mice did increase WNK kinase levels and the abundance of phosphorylated Na-Cl cotransporter (NCC). Over time, however, Cul3 deletion caused renal dysfunction, including hypochloremic alkalosis, diabetes insipidus, and salt-sensitive hypotension, with depletion of sodium potassium chloride cotransporter 2 and aquaporin 2. Moreover, these animals exhibited renal inflammation, fibrosis, and increased cyclin E. These results indicate that FHHt-associated CUL3 Δ403-459 targets KLHL3 for degradation, thereby preventing WNK degradation, whereas general loss of CUL3 activity - while also impairing WNK degradation - has widespread toxic effects in the kidney.
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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.