Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans
| Autor: | Manfred Gessler, Seon-Ho Ahn, James Pullman, Han Si, Bernhard Bielesz, Hideki Kato, Volker H. Haase, Yasemin Sirin, Thiruvur Niranjan, Antje Gruenwald, Katalin Susztak |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
Pathology medicine.medical_specialty Notch signaling pathway Mice Transgenic Kidney Mice Fibrosis Basic Helix-Loop-Helix Transcription Factors Renal fibrosis medicine Animals Humans Serrate-Jagged Proteins Receptor Notch1 Cell Proliferation Homeodomain Proteins biology Calcium-Binding Proteins Membrane Proteins Kidney metabolism Epithelial Cells General Medicine medicine.disease Kidney Tubules medicine.anatomical_structure Cancer research biology.protein Tubulointerstitial fibrosis Intercellular Signaling Peptides and Proteins Kidney Failure Chronic Nephritis Interstitial Transcription Factor HES-1 Amyloid Precursor Protein Secretases Signal transduction Amyloid precursor protein secretase Research Article Signal Transduction |
| Zdroj: | Journal of Clinical Investigation. 120:4040-4054 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci43025 |
| Popis: | Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a γ-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development. |
| Databáze: | OpenAIRE |
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