1. Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans.
- Author
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Bielesz B, Sirin Y, Si H, Niranjan T, Gruenwald A, Ahn S, Kato H, Pullman J, Gessler M, Haase VH, and Susztak K
- Subjects
- Amyloid Precursor Protein Secretases antagonists & inhibitors, Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Cell Proliferation, Epithelial Cells cytology, Fibrosis pathology, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Kidney cytology, Kidney Failure, Chronic metabolism, Kidney Failure, Chronic pathology, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Transgenic, Nephritis, Interstitial metabolism, Nephritis, Interstitial pathology, Receptor, Notch1 genetics, Serrate-Jagged Proteins, Transcription Factor HES-1, Epithelial Cells metabolism, Kidney metabolism, Kidney pathology, Kidney Tubules cytology, Receptor, Notch1 metabolism, Signal Transduction physiology
- Abstract
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.
- Published
- 2010
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