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Vascular endothelial growth factor-A165b restores normal glomerular water permeability in a diphtheria-Toxin mouse model of glomerular injury

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)51-62
Number of pages12
JournalNephron Physiology
Volume139
Issue number1
Early online date26 Jan 2018
DOIs
DateAccepted/In press - 24 Nov 2017
DateE-pub ahead of print - 26 Jan 2018
DatePublished (current) - 1 Apr 2018

Abstract

Background/Aims: 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-A165b). Methods: The Pod-DTR mouse was crossed with a mouse that over-expressed VEGF-A165b specifically in the podocytes (Neph-VEGF-A165b). Wild type (WT), Pod-DTR, Neph-VEGF-A165b and Pod-DTR X Neph-VEGF-A165b 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 (LpA/Vi) was measured ex vivo after 14 days. Structural analysis and podocyte marker expression were also assessed. Results: Pod-DTR mice developed an increased glomerular LpA/Vi 14 days after administration of DT (all doses), which was prevented when the mice over-expressed VEGF-A165b. 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-A165b mice. Conclusion: Although only a mild model of podocyte injury, over-expression of the anti-permeability VEGF-A165b isoform in the podocytes of Pod-DTR mice had a protective effect. Therefore, this study further highlights the therapeutic potential of VEGF-A165b in glomerular disease.

    Research areas

  • Diphtheria-Toxin, Glomerulus, Permeability, Podocyte, Vascular endothelial growth factor-Ab

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Karger at https://doi.org/10.1159/000485664 . Please refer to any applicable terms of use of the publisher.

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    Licence: CC BY

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