• 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>&lt;i&gt;Background:&lt;/i&gt; Notch receptors are involved in kidney development and pathogenesis of inflammatory glomerular diseases. Given the secretion of Y-&lt;i&gt;box&lt;/i&gt; (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. &lt;i&gt;Methods:&lt;/i&gt; 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&lt;sup&gt;+/d&lt;/sup&gt;) 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. &lt;i&gt;Results:&lt;/i&gt; 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&lt;sup&gt;+/d&lt;/sup&gt; 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. &lt;i&gt;Conclusion:&lt;/i&gt; 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>&lt;i&gt;Background:&lt;/i&gt; Notch receptors are involved in kidney development and pathogenesis of inflammatory glomerular diseases. Given the secretion of Y-&lt;i&gt;box&lt;/i&gt; (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. &lt;i&gt;Methods:&lt;/i&gt; 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&lt;sup&gt;+/d&lt;/sup&gt;) 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. &lt;i&gt;Results:&lt;/i&gt; 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&lt;sup&gt;+/d&lt;/sup&gt; 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. &lt;i&gt;Conclusion:&lt;/i&gt; 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>
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