Journal Article

Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans

Gruenwald, Antje, Kato, Hideki, Susztak, Katalin, Si, Han, Gessler, Manfred, Bielesz, Bernhard, Sirin, Yasemin, Niranjan, Thiruvur, Pullman, James, Ahn, Seonho, Haase, Volker H.

2010

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Amyloid Precursor Protein Secretases - antagonists & inhibitors / Analysis / Animals / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - metabolism / Biomedical research / Calcium-Binding Proteins - genetics / Calcium-Binding Proteins - metabolism / Cell Proliferation / Cellular signal transduction / Chronic kidney failure / Complications and side effects / Development and progression / Epithelial Cells - cytology / Epithelial Cells - metabolism / Experiments / Fibroblasts / Fibrosis / Fibrosis - pathology / Gene expression / Genetic aspects / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humans / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Kidney - cytology / Kidney - metabolism / Kidney - pathology / Kidney diseases / Kidney Failure, Chronic - metabolism / Kidney Failure, Chronic - pathology / Kidney Tubules - cytology / Ligands / Male / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / Mice, Transgenic / Nephritis, Interstitial - metabolism / Nephritis, Interstitial - pathology / Physiological aspects / Receptor, Notch1 - genetics / Receptor, Notch1 - metabolism / Risk factors / Serrate-Jagged Proteins / Signal Transduction - physiology / Transcription Factor HES-1