ArticleScientific reports2017
NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Fibrocystin/polyductin (FPC): new functional insights into ARPKD pathogenesis revealed by informatics, comparative genomics, and model systems.Pediatric nephrology (Berlin, Germany) · 2026Review
- Modeling Complex Developmental Disease: The Case of Polycystic Kidney Disease.Journal of developmental biology · 2026Review
- Epithelial cell expansion drives cyst progression in genetic models of autosomal recessive polycystic kidney disease.iScience · 2026Article
- Genome-Based Advances in Modeling Renal Ciliopathies and Enhancing Patient Care.Kidney & blood pressure research · 2025Review
- NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases.Biomolecules · 2024Review
- Defects of renal tubular homeostasis and cystogenesis in theiScience · 2024Article
- Review
- Pkhd1Journal of molecular medicine (Berlin, Germany) · 2023Article
- Cystin is required for maintaining fibrocystin (FPC) levels and safeguarding proteome integrity in mouse renal epithelial cells: A mechanistic connection between the kidney defects in cpk mice and human ARPKD.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2023Article
- Ion channels as a therapeutic target for renal fibrosis.Frontiers in physiology · 2022Review
- Recent advances in understanding ion transport mechanisms in polycystic kidney disease.Clinical science (London, England : 1979) · 2021Review
- Predictors of progression in autosomal dominant and autosomal recessive polycystic kidney disease.Pediatric nephrology (Berlin, Germany) · 2021Review
- Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease.International journal of molecular sciences · 2021Review
- Use of patient derived urine renal epithelial cells to confirm pathogenicity of PKHD1 alleles.BMC nephrology · 2020Article
- Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment.International journal of molecular sciences · 2020Review
- Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease.The Journal of biological chemistry · 2019Article
- Loss of primary cilia increases polycystin-2 and TRPV4 and the appearance of a nonselective cation channel in the mouse cortical collecting duct.American journal of physiology. Renal physiology · 2019Article
- Salt-deficient diet exacerbates cystogenesis in ARPKD via epithelial sodium channel (ENaC).EBioMedicine · 2019Article
- Increased salt intake does not worsen the progression of renal cystic disease in high water-loaded PCK rats.PloS one · 2019Article
Corrections and comments
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Authors and funding
19 authors at 11 institutions in 5 countries.
Funding
Abstract
Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births. The major clinical phenotypes are expressed in the kidney with dilatation of the collecting ducts, systemic hypertension, and progressive renal insufficiency, and in the liver with biliary dysgenesis, portal tract fibrosis, and portal hypertension. The systemic hypertension has been attributed to enhanced distal sodium reabsorption in the kidney, the structural defects have been ascribed to altered cellular morphology, and fibrosis to increased TGF-β signaling in the kidney and biliary tract, respectively. The pathogenic mechanisms underlying these abnormalities have not been determined. In the current report, we find that disrupting PKHD1 results in altered sub-cellular localization and function of the C2-WWW-HECT domain E3 family of ligases regulating these processes. We also demonstrate altered activity of RhoA and increased TGF-β signaling and ENaC activity. Linking these phenomena, we found that vesicles containing the PKHD1/Pkhd1 gene product, FPC, also contain the NEDD4 ubiquitin ligase interacting protein, NDFIP2, which interacts with multiple members of the C2-WWW-HECT domain E3 family of ligases. Our results provide a mechanistic explanation for both the cellular effects and in vivo phenotypic abnormalities in mice and humans that result from Pkhd1/PKHD1 mutation.
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Registered trials
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