ArticleAmerican journal of physiology. Renal physiology2008
Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2.
Article in American journal of physiology. Renal physiology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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86 citing papers in PubMed, 155 citations in OpenAlex.
- Renal Tubule Cell-SpecificHypertension (Dallas, Tex. : 1979) · 2026Article
- NEDD4L Suppresses Proliferation and Promotes Apoptosis by Ubiquitinating RAC2 Expression and Acts as a Prognostic Biomarker in Clear Cell Renal Cell Carcinoma.International journal of molecular sciences · 2024Article
- Angiotensin-Converting Enzyme 2 Posttranslational Modifications and Implications for Hypertension and SARS-CoV-2: 2023 Lewis K. Dahl Memorial Lecture.Hypertension (Dallas, Tex. : 1979) · 2024Review
- Ubiquitination of NKCC2 by the cullin-RING E3 ubiquitin ligase family in the thick ascending limb of the loop of Henle.American journal of physiology. Renal physiology · 2023Article
- NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor.Frontiers in pharmacology · 2023Review
- Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.Journal of clinical hypertension (Greenwich, Conn.) · 2022Article
- Elevated intracellular NaProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Research progress of Nedd4L in cardiovascular diseases.Cell death discovery · 2022Review
- Review
- E3 ubiquitin ligase Nedd4-2 exerts neuroprotective effects during endoplasmic reticulum stress.Journal of neurochemistry · 2022Article
- Does the early aldosterone-induced SGK1 play a role in early Kaliuresis?Physiological reports · 2022Article
- The E3 ubiquitin-protein ligase Nedd4-2 regulates the sodium chloride cotransporter NCC but is not required for a potassium-induced reduction of NCC expression.Frontiers in physiology · 2022Article
- ROMK channels are inhibited in the aldosterone-sensitive distal nephron of renal tubule Nedd4-2-deficient mice.American journal of physiology. Renal physiology · 2022Article
- The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease.International journal of molecular sciences · 2021Review
- Role of the Ubiquitin Proteasome System in the Regulation of Blood Pressure: A Review.International journal of molecular sciences · 2020Review
- The Renal Physiology of Pendrin-Positive Intercalated Cells.Physiological reviews · 2020Review
- Renal Tubule Nedd4-2 Deficiency Stimulates Kir4.1/Kir5.1 and Thiazide-Sensitive NaCl Cotransporter in Distal Convoluted Tubule.Journal of the American Society of Nephrology : JASN · 2020Article
- DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells.Circulation · 2020Article
- NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor.The EMBO journal · 2020Article
- E3 Ubiquitin ligase NEDD4 family‑regulatory network in cardiovascular disease.International journal of biological sciences · 2020Review
26 more citing papers are in PubMed but not listed here.
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14 authors at 1 institution in 1 country.
Funding
Abstract
Nedd4-2 has been proposed to play a critical role in regulating epithelial Na+ channel (ENaC) activity. Biochemical and overexpression experiments suggest that Nedd4-2 binds to the PY motifs of ENaC subunits via its WW domains, ubiquitinates them, and decreases their expression on the apical membrane. Phosphorylation of Nedd4-2 (for example by Sgk1) may regulate its binding to ENaC, and thus ENaC ubiquitination. These results suggest that the interaction between Nedd4-2 and ENaC may play a crucial role in Na+ homeostasis and blood pressure (BP) regulation. To test these predictions in vivo, we generated Nedd4-2 null mice. The knockout mice had higher BP on a normal diet and a further increase in BP when on a high-salt diet. The hypertension was probably mediated by ENaC overactivity because 1) Nedd4-2 null mice had higher expression levels of all three ENaC subunits in kidney, but not of other Na+ transporters; 2) the downregulation of ENaC function in colon was impaired; and 3) NaCl-sensitive hypertension was substantially reduced in the presence of amiloride, a specific inhibitor of ENaC. Nedd4-2 null mice on a chronic high-salt diet showed cardiac hypertrophy and markedly depressed cardiac function. Overall, our results demonstrate that in vivo Nedd4-2 is a critical regulator of ENaC activity and BP. The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder.
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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.