Notch-3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury.
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.
Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
Sonja
S
Djudjaj
Christos
C
Chatziantoniou
Ute
U
Raffetseder
Dominique
D
Guerrot
Jean-Claude
JC
Dussaule
Peter
P
Boor
Monique
M
Kerroch
Lydia
L
Hanssen
Sabine
S
Brandt
Annemarie
A
Dittrich
Tammo
T
Ostendorf
Jürgen
J
Floege
Cheng
C
Zhu
Maja
M
Lindenmeyer
Clemens D
CD
Cohen
Peter R
PR
Mertens
D000818:Animals; D001706:Biopsy; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072101:Jagged-2 Protein; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D051881:Receptor, Notch1 / Q000502:physiology; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D036341:Intercellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C499374:NOTCH3 protein, human; C499373:Notch3 protein, mouse; C498556:Notch3 protein, rat; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta