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Raffetseder, Ute;
Rauen, Thomas;
Boor, Peter;
Ostendorf, Tammo;
Hanssen, Lydia;
Floege, Jürgen;
En-Nia, Abdelaziz;
Djudjaj, Sonja;
Frye, Björn C.;
Mertens, Peter R.
Extracellular YB-1 Blockade in Experimental Nephritis Upregulates Notch-3 Receptor Expression and Signaling
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- Medientyp: E-Artikel
- Titel: Extracellular YB-1 Blockade in Experimental Nephritis Upregulates Notch-3 Receptor Expression and Signaling
- Beteiligte: Raffetseder, Ute; Rauen, Thomas; Boor, Peter; Ostendorf, Tammo; Hanssen, Lydia; Floege, Jürgen; En-Nia, Abdelaziz; Djudjaj, Sonja; Frye, Björn C.; Mertens, Peter R.
- Erschienen: S. Karger AG, 2011
- Erschienen in: Nephron Experimental Nephrology
- Umfang: e100-e108
- Sprache: Englisch
- DOI: 10.1159/000324209
- ISSN: 1660-2129
- Schlagwörter: Nephrology ; Genetics ; Physiology ; General Medicine
- Zusammenfassung: <jats:p><i>Background:</i> Notch receptors are involved in kidney development and pathogenesis of inflammatory glomerular diseases. Given the secretion of Y-<i>box</i> (YB) protein-1 following cytokine stimulation and subsequent extracellular association with membrane receptor Notch-3 in vitro, we elucidated functional effects of YB-1 targeting on the Notch-3 signaling pathway. <i>Methods:</i> Rat mesangial cells were challenged with a monoclonal anti-YB-1 antibody (YB-1-mAb) and analyzed for YB-1 and Notch-3 expression. Notch-3 expression in mice with a targeted disruption of one YB-1 allele (YB-1<sup>+/d</sup>) was compared with their wild-type littermates. Furthermore, YB-1-mAb was applied during mesangioproliferative anti-Thy1.1 nephritis, and glomerular Notch-3, Notch target genes and YB-1 expression were analyzed by immunohistochemistry, quantitative real-time PCR and immunoblotting. <i>Results:</i> Upon challenge with YB-1-mAb, rat mesangial cells showed an increased expression of YB-1 and Notch-3 protein. Concordantly, we found a significant upregulation of Notch-3 expression in renal cells of YB-1<sup>+/d</sup> mice. YB-1-mAb treatment in anti-Thy1.1 nephritis resulted in enhanced mesangial Notch-3 expression and differential Notch target gene activation (HES2/Hey-2). Notably, YB-1 mRNA content did not differ between groups; however, glomerular YB-1 protein was significantly increased, suggesting a posttranslational mechanism. <i>Conclusion:</i> Extracellular targeting of YB-1 potently induces glomerular Notch-3 receptor expression, Notch signaling and YB-1 stabilization, most likely via an autoregulatory feedback mechanism.</jats:p>
- Beschreibung: <jats:p><i>Background:</i> Notch receptors are involved in kidney development and pathogenesis of inflammatory glomerular diseases. Given the secretion of Y-<i>box</i> (YB) protein-1 following cytokine stimulation and subsequent extracellular association with membrane receptor Notch-3 in vitro, we elucidated functional effects of YB-1 targeting on the Notch-3 signaling pathway. <i>Methods:</i> Rat mesangial cells were challenged with a monoclonal anti-YB-1 antibody (YB-1-mAb) and analyzed for YB-1 and Notch-3 expression. Notch-3 expression in mice with a targeted disruption of one YB-1 allele (YB-1<sup>+/d</sup>) was compared with their wild-type littermates. Furthermore, YB-1-mAb was applied during mesangioproliferative anti-Thy1.1 nephritis, and glomerular Notch-3, Notch target genes and YB-1 expression were analyzed by immunohistochemistry, quantitative real-time PCR and immunoblotting. <i>Results:</i> Upon challenge with YB-1-mAb, rat mesangial cells showed an increased expression of YB-1 and Notch-3 protein. Concordantly, we found a significant upregulation of Notch-3 expression in renal cells of YB-1<sup>+/d</sup> mice. YB-1-mAb treatment in anti-Thy1.1 nephritis resulted in enhanced mesangial Notch-3 expression and differential Notch target gene activation (HES2/Hey-2). Notably, YB-1 mRNA content did not differ between groups; however, glomerular YB-1 protein was significantly increased, suggesting a posttranslational mechanism. <i>Conclusion:</i> Extracellular targeting of YB-1 potently induces glomerular Notch-3 receptor expression, Notch signaling and YB-1 stabilization, most likely via an autoregulatory feedback mechanism.</jats:p>
- Anmerkungen: