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

J Clin Invest. 2010 Nov;120(11):4040-54. doi: 10.1172/JCI43025. Epub 2010 Oct 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Epithelial Cells / metabolism*
  • Fibrosis / pathology
  • 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 Failure, Chronic / metabolism
  • Kidney Failure, Chronic / pathology
  • Kidney Tubules / cytology*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Nephritis, Interstitial / metabolism
  • Nephritis, Interstitial / pathology
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction / physiology*
  • Transcription Factor HES-1

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium-Binding Proteins
  • Hes1 protein, mouse
  • Heyl protein, mouse
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NOTCH1 protein, human
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Serrate-Jagged Proteins
  • Transcription Factor HES-1
  • Amyloid Precursor Protein Secretases