Notch-3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury.

Abstract

Kidney diseases impart a vast burden on affected individuals and the overall health care system. Progressive loss of renal parenchymal cells and functional decline following injury are often observed. Notch-1 and -2 receptors are crucially involved in nephron development and contribute to inflammatory kidney diseases. We specifically determined the participation of receptor Notch-3 following tubulointerstitial injury and in inflammatory responses. Here we show by heat map analyses that Notch-3 transcripts are up-regulated in human kidney diseases. A similar response was corroborated with kidney cells following TGF-β exposure in vitro. The murine unilateral ureteral obstruction (UUO) model mirrors hallmarks of tubulointerstitial injury and damage. A subset of tubular and interstitial cells demonstrated up-regulated Notch-3 receptor expression in diseased animals. We hypothesized a relevance of Notch-3 receptors for the chemotactic response. To address this question, animals with genetic ablation of receptor Notch-3 were analysed following UUO. As a result, we found that Notch-3-deficient animals are protected from tubular injury and cell loss with significantly reduced interstitial collagen deposition. Monocytic cell infiltration was significantly reduced and retarded, likely due to abrogated chemokine synthesis. A cell model was set up that mimics enhanced receptor Notch-3 expression and activation. Here a pro-mitogenic response was seen with activated signalling in tubular cells and fibroblasts. In conclusion, Notch-3 receptor fulfils non-redundant roles in the inflamed kidney that may not be replaced by other Notch receptor family members. Thus, specific blockade of this receptor may be suitable as therapeutic option to delay progression of kidney disease.

• Authors: Sonja Djudjaj, Christos Chatziantoniou, Ute Raffetseder, Dominique Guerrot, Jean-Claude Dussaule, Peter Boor, Monique Kerroch, Lydia Hanssen, Sabine Brandt, Annemarie Dittrich, Tammo Ostendorf, Jürgen Floege, Cheng Zhu, Maja Lindenmeyer, Clemens D Cohen, Peter R Mertens
• Journal: The Journal of pathology (J Pathol) Vol. 228 Issue 3 Pg. 286-99 (Nov 2012) ISSN: 1096-9896 [Electronic] England
• PMID: 22806125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Intercellular Signaling Peptides and Proteins
• JAG2 protein, human
• Jagged-2 Protein
• Membrane Proteins
• NOTCH3 protein, human
• Notch3 protein, mouse
• Notch3 protein, rat
• Receptor, Notch1
• Receptor, Notch3
• Receptors, Notch
• Transforming Growth Factor beta

Topics

• Animals
• Biopsy
• Cell Line
• Cell Proliferation
• Disease Models, Animal
• Female
• Fibrosis
• Humans
• In Vitro Techniques
• Inflammation (physiopathology)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Jagged-2 Protein
• Kidney (metabolism, pathology, physiopathology)
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nephritis, Interstitial (metabolism, pathology, physiopathology)
• Rats
• Receptor, Notch1 (physiology)
• Receptor, Notch3
• Receptors, Notch (deficiency, genetics, physiology)
• Signal Transduction (physiology)
• Transforming Growth Factor beta (pharmacology)
• Up-Regulation (drug effects)
• Ureteral Obstruction (metabolism, pathology, physiopathology)