ArticleJCI insight2016
ADAM17 substrate release in proximal tubule drives kidney fibrosis.
Article in JCI insight, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05997641 (A Double-Blind, Randomized, Placebo-Controlled, First-in-Human Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Orally Administered DF-003 Following Single), which is not on this map. Cited by 72 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Double-Blind, Randomized, Placebo-Controlled, First-in-Human Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Orally Administered DF-003 Following Single (Part 1) and Multiple (Part 2) Ascending Doses in Healthy Subjects
Who cites it
72 citing papers in PubMed, 127 citations in OpenAlex.
- The Role of Aryl Hydrocarbon Receptor-Dependent Signaling Pathway in the Profibrotic Effects of Dioxin-like Compounds in Human Renal Tubular Epithelial Cells.Environment & health (Washington, D.C.) · 2026Article
- Temporal inhibition of ADAM17 in fibroblasts reduces stiffness and promotes vascularization following myocardial infarction.Cardiovascular research · 2026Article
- Amphiregulin in Fibrotic Diseases and Cancer.International journal of molecular sciences · 2025Review
- Kidney deletions of Cyp27b1 fail to reduce serum 1,25(OH)The Journal of steroid biochemistry and molecular biology · 2025Article
- Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury.The Journal of clinical investigation · 2025Review
- CD133+CD24+ Renal Tubular Progenitor Cells Drive Hypoxic Injury Recovery via Hypoxia-Inducible Factor-1A and Epidermal Growth Factor Receptor Expression.International journal of molecular sciences · 2025Article
- Treg derived Amphiregulin protects from murine lupus nephritis via tissue reparative effects.Scientific reports · 2025Article
- Progress of ADAM17 in Fibrosis-Related Diseases.Mediators of inflammation · 2025Review
- Mesenchymal stem cell-derived extracellular vesicles ameliorate renal interstitial fibrosis via the miR-13474/ADAM17 axis.Scientific reports · 2024Article
- Article
- Clinical significance of amphiregulin in patients with chronic kidney disease.Clinical and experimental nephrology · 2024Article
- Combination of ADAM17 knockdown with eplerenone is more effective than single therapy in ameliorating diabetic cardiomyopathy.Frontiers in pharmacology · 2024Article
- Targeting the epidermal growth factor receptor (EGFR/ErbB) for the potential treatment of renal pathologies.Frontiers in pharmacology · 2024Review
- IL-6 and diabetic kidney disease.Frontiers in immunology · 2024Review
- Cep120 is essential for kidney stromal progenitor cell growth and differentiation.EMBO reports · 2024Article
- Epidermal growth factor receptor activation is essential for kidney fibrosis development.Nature communications · 2023Article
- MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice.Nature communications · 2023Article
- Targeting IL-6 trans-signalling: past, present and future prospects.Nature reviews. Immunology · 2023Review
- Article
- EGF-Receptor-Dependent TLR7 Signaling in Macrophages Promotes Glomerular Injury in Crescentic Glomerulonephritis.Laboratory investigation; a journal of technical methods and pathology · 2023Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible KO of ADAM17 in proximal tubule (Slc34a1-Cre) were significantly protected against these effects. In vitro, in proximal tubule cells, we show that AREG has unique profibrotic actions that are potentiated by TNFα-induced AREG cleavage. In vivo, in acute kidney injury (AKI) and chronic kidney disease (CKD, fibrosis) patients, soluble AREG is indeed highly upregulated in human urine, and both ADAM17 and AREG expression show strong positive correlation with fibrosis markers in related kidney biopsies. Our results indicate that targeting of the ADAM17 pathway represents a therapeutic target for human kidney fibrosis.
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Registered trials
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.