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Untersuchungen zur Rolle von Notch-3 Rezeptoren in experimentellen Schädigungsmodellen der Niere

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Publikationsserver der RWTH Aachen University
Keywords
  • Info:Eu-Repo/Classification/Ddc/570
  • Entzündung
  • Schädigung
  • Niere
  • Fibrose
  • Nierenkrankheit
  • Biowissenschaften, Biologie
  • Notch-3
  • Renale Fibrose
  • Nierenfibrose
  • Inflammation
  • Kidney Fibrosis
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Abstract

Kidney disease imparts a vast burden on affected individuals and the overall health care system. Progressive tubulointerstitial fibrosis represents a common final pathway observed in all forms of chronic kidney diseases, characterized by deposition of extracellular matrix, immune cell infiltration, fibroblast proliferation and activation, injury to the tubular epithelium and rarefaction of the peritubular microvasculature. In the recent past, Notch receptors, which are involved in the nephron development, attributed increasingly a significant role in the development of various kidney diseases, and also in the tubulointerstitial fibrosis. In the present work, the involvement of the receptor Notch-3 in the immune cell response and kidney fibrosis was examined. First evidence for an involvement of Notch-3 receptor on the fibrogenesis was shown by in vitro studies in cultured kidney cells. Stimulation with the central profibrotic mediator TGF-beta1 resulted in an increased expression of the receptor Notch-1 and Notch-3 and so on both transcription and protein level. This has been confirmed in vivo in two different animal models of renal damage, the nephrotoxic nephritis (NTN) and the unilateral ureteral obstruction (UUO). The NTN is a primary inflammatory, glomerular and thus proteinuric model whose profile corresponds to a rapidly progressive glomerulonephritis. In addition to the glomerular injury it results in tubulointerstitial immune cell infiltration and fibrosis. The murine UUO model primarily caused damage to the tubular structures and also reflects the hallmarks of tubulointerstitial fibrosis. In both models an activation of the Notch-3 receptor, and increased expression of Notch ligands and target genes was detectable. Striking is, that the increased expression of Notch-3 occurred cell-specific and so after ureteral obstruction detected only in isolated tubular and in some tubulointerstitial. cells. This suggests that the Notch-3-mediated regulatory events are controlled only by subpopulations of cells. We hypothesized that Notch-3 plays a functional relevance in the chemotactic response. Therefore, we studied animals with genetic depletion of Notch-3 receptor after UUO and NTN induction. We could show that Notch-3 knockout (Notch-3 KO) mice were protected from injury and tubular cell loss. The infiltration of inflammatory cells was significantly reduced and delayed, presumably due to a reduced chemokine synthesis and release. The Notch-3 knockout mice also exhibited a very significant reduction in the matrix accumulation that is due to reduced proliferation of interstitial cells. To investigate a direct influence of Notch-3 receptor on the cell proliferation, a cell model was established, which simulates an increased Notch-3 expression/ activation. Overexpression of constitutively active intracellular Notch-3 domain increased proliferation rate of renal tubular cells in vitro. This result was confirmed by incubating the cells with the Notch ligand Jagged-1. In addition to the in vivo and in vitro studies in a third approach, we correlated the expression of members of the Notch receptor family with human renal diseases. Human biopsies of patients with tubular and glomerular kidney diseases have been studied in terms of a gene array where mRNA expression of Notch signal pathways components were measured and hence a heat map was created. It was found that Notch-3 was expressed strongest by all of the Notch family receptors. In summary, our results show that the Notch-3 receptor plays an important role in the orchestration of tubulointerstitial, inflammatory response and in particular the monocytic cell infiltration is affected by Notch-3. This makes the Notch pathway an attractive target for future therapeutic interventions in which an excessive matrix deposition and the consequent destruction of the tissue architecture is to be countered.

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