Notch-3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury. - Archive ouverte HAL Access content directly
Journal Articles Journal of Pathology Year : 2012

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

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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.
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Dates and versions

inserm-00771471 , version 1 (08-01-2013)

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Sonja Djudjaj, Christos Chatziantoniou, Ute Raffetseder, Dominique Guerrot, Jean-Claude Dussaule, et al.. Notch-3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury.: Notch-3 receptor and inflammatory kidney diseases. Journal of Pathology, 2012, 228 (3), pp.286-99. ⟨10.1002/path.4076⟩. ⟨inserm-00771471⟩
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