ArticleThe Journal of clinical investigation2013
Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension.
Article in The Journal of clinical investigation, 2013. 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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Who cites it
86 citing papers in PubMed, 140 citations in OpenAlex.
- The kidney distal tubule potassium switch, modern diet and hypertension.Nature reviews. Nephrology · 2026Review
- Adaptor-mediated interaction between Kv1.3 and Nedd4-2 E3 ubiquitin ligase.Communications biology · 2026Article
- Increased Urinary Extracellular Vesicles and Reduced Expression of NEDD4L in Patients With Type 2 Diabetes and Diabetic Nephropathy.Journal of diabetes research · 2026Article
- Hypomagnesaemia-associated hypokalaemia requires activation of both ENaC and ROMK.The Journal of physiology · 2025Article
- Animal models of hypertension and concurrent organs injury.Animal models and experimental medicine · 2025Review
- Beyond Blood Pressure: Emerging Pathways and Precision Approaches in Hypertension-Induced Kidney Damage.International journal of molecular sciences · 2025Review
- PRDM16 deficiency promotes podocyte injury by impairing insulin receptor signaling.Cell death and differentiation · 2025Article
- Silencing NEDD4L Effectively Inhibits the Malignant Behaviors of Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2025Article
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity.The Journal of cell biology · 2024Article
- Aldosterone: Renal Action and Physiological Effects.Comprehensive Physiology · 2023Article
- Urine Cell Transcriptomes Implicate Specific Renal Inflammatory Pathways Associated With Difficult-to-Control Hypertension.Journal of the American Heart Association · 2023Article
- 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
- Molecular Mechanisms of Na-Cl Cotransporter in Relation to Hypertension in Chronic Kidney Disease.International journal of molecular sciences · 2022Review
- In Primary Aldosteronism Acute Potassium Chloride Supplementation Suppresses Abundance and Phosphorylation of the Sodium-Chloride Cotransporter.Kidney360 · 2022Article
- 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
- Regulation of distal tubule sodium transport: mechanisms and roles in homeostasis and pathophysiology.Pflugers Archiv : European journal of physiology · 2022Review
- Genetic Modifications to Alter Blood Pressure Level.Biomedicines · 2022Review
- Elevated intracellular NaProceedings of the National Academy of Sciences of the United States of America · 2022Article
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26 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK.
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