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Stevens, Megan; Neal, Christopher R.; Salmon, Andrew H.J.; Bates, David O.; Harper, Steven J.; Oltean, Sebastian

Vascular Endothelial Growth Factor-A165b Restores Normal Glomerular Water Permeability in a Diphtheria-Toxin Mouse Model of Glomerular Injury

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  • Media type: E-Article
  • Title: Vascular Endothelial Growth Factor-A165b Restores Normal Glomerular Water Permeability in a Diphtheria-Toxin Mouse Model of Glomerular Injury
  • Contributor: Stevens, Megan; Neal, Christopher R.; Salmon, Andrew H.J.; Bates, David O.; Harper, Steven J.; Oltean, Sebastian
  • imprint: S. Karger AG, 2018
  • Published in: Nephron
  • Language: English
  • DOI: 10.1159/000485664
  • ISSN: 1660-8151; 2235-3186
  • Origination:
  • Footnote:
  • Description: <jats:p>&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt;&lt;i&gt;&lt;/i&gt; Genetic cell ablation using the human diphtheria toxin receptor (hDTR) is a new strategy used for analysing cellular function. Diphtheria toxin (DT) is a cytotoxic protein that leaves mouse cells relatively unaffected, but upon binding to hDTR it ultimately leads to cell death. We used a podocyte-specific hDTR expressing (Pod-DTR) mouse to assess the anti-permeability and cyto-protective effects of the splice isoform vascular endothelial growth factor (VEGF-A&lt;sub&gt;165&lt;/sub&gt;b). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt;&lt;i&gt;&lt;/i&gt; The Pod-DTR mouse was crossed with a mouse that over-expressed VEGF-A&lt;sub&gt;165&lt;/sub&gt;b specifically in the podocytes (Neph-VEGF-A&lt;sub&gt;165&lt;/sub&gt;b). Wild type (WT), Pod-DTR, Neph-VEGF-A&lt;sub&gt;165&lt;/sub&gt;b and Pod-DTR X Neph-VEGF-A&lt;sub&gt;165&lt;/sub&gt;b mice were treated with several doses of DT (1, 5, 100, and 1,000 ng/g bodyweight). Urine was collected and the glomerular water permeability (L&lt;sub&gt;p&lt;/sub&gt;A/V&lt;sub&gt;i&lt;/sub&gt;) was measured ex vivo after 14 days. Structural analysis and podocyte marker expression were also assessed. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt;&lt;i&gt;&lt;/i&gt; Pod-DTR mice developed an increased glomerular L&lt;sub&gt;p&lt;/sub&gt;A/V&lt;sub&gt;i&lt;/sub&gt; 14 days after administration of DT (all doses), which was prevented when the mice over-expressed VEGF-A&lt;sub&gt;165&lt;/sub&gt;b. No major structural abnormalities, podocyte ablation or albuminuria was observed in Pod-DTR mice, indicating this to be a mild model of podocyte disease. However, a change in expression and localisation of nephrin within the podocytes was observed, indicating disruption of the slit diaphragm in the Pod-DTR mice. This was prevented in the Pod-DTR X Neph-VEGF-A&lt;sub&gt;165&lt;/sub&gt;b mice. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt;&lt;i&gt;&lt;/i&gt; Although only a mild model of podocyte injury, over-expression of the anti-permeability VEGF-A&lt;sub&gt;165&lt;/sub&gt;b isoform in the podocytes of Pod-DTR mice had a protective effect. Therefore, this study further highlights the therapeutic potential of VEGF-A&lt;sub&gt;165&lt;/sub&gt;b in glomerular disease.</jats:p>