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

Autor: Djudjaj, Sonja, Chatziantoniou, Christos, Raffetseder, Ute, Guerrot, Dominique, Dussaule, Jean-Claude, Boor, Peter, Kerroch, Monique, Hanssen, Lydia, Brandt, Sabine, Dittrich, Anne-Marie, Ostendorf, Tammo, Floege, Jürgen, Zhu, Cheng, Lindenmeyer, Maja, Cohen, Clemens, Mertens, Peter
Přispěvatelé: Chatziantoniou, Christos, Department of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology, Institute of Molecular Biomedicine, Comenius University in Bratislava, Department of Medical Microbiology, Division of nephrology and Institute of Physiology, Universität Zürich [Zürich] = University of Zurich (UZH), This work was supported by fellowship grants from the ERA-ETDA (to S.D.), DFG SFB 854 project 01 (to P.R.M.) and DFG Sachbeihilfeantrag 1365/7-1 (to P.R.M.). C.C. received INSERM funding. U.R was funded by the Else-Kröner-Fresenius- Stiftung.
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Zdroj: Journal of Pathology
Journal of Pathology, 2012, 228 (3), pp.286-99. ⟨10.1002/path.4076⟩
ISSN: 0022-3417
1096-9896
DOI: 10.1002/path.4076⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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