dc.contributor.author | Stevens, M | |
dc.contributor.author | Neal, CR | |
dc.contributor.author | Salmon, AHJ | |
dc.contributor.author | Bates, DO | |
dc.contributor.author | Harper, SJ | |
dc.contributor.author | Oltean, S | |
dc.date.accessioned | 2018-04-27T07:49:56Z | |
dc.date.issued | 2018-01-26 | |
dc.description.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. | en_GB |
dc.description.sponsorship | Funding for this study was supported by BBSRC (BB/
J007293/2), the Medical Research Council (G10002073), British
Heart Foundation (PG/15/53/31371), and Richard Bright VEGF
Research Trust. | en_GB |
dc.identifier.citation | Vol.139, pp.51–62 | en_GB |
dc.identifier.doi | 10.1159/000485664 | |
dc.identifier.uri | http://hdl.handle.net/10871/32627 | |
dc.language.iso | en | en_GB |
dc.publisher | Karger Publishers | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/29393270 | en_GB |
dc.rights | © 2018 The Author(s)
Published by S. Karger AG, Basel
This article is licensed under the Creative Commons Attribution 4.0
International License (CC BY) (http://www.karger.com/Services/
OpenAccessLicense). Usage, derivative works and distribution are
permitted provided that proper credit is given to the author and the
original publisher. | en_GB |
dc.subject | Diphtheria-toxin | en_GB |
dc.subject | Glomerulus | en_GB |
dc.subject | Permeability | en_GB |
dc.subject | Podocyte | en_GB |
dc.subject | Vascular endothelial growth factor-A165b | en_GB |
dc.title | Vascular endothelial growth factor-A165b restores normal glomerular water permeability in a diphtheria-toxin mouse model of glomerular Injury. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2018-04-27T07:49:56Z | |
exeter.place-of-publication | Switzerland | en_GB |
dc.description | This is the final version of the article. Available from the publisher via the DOI in this record. | en_GB |
dc.identifier.journal | Nephron | en_GB |