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Deciphering the Mechanisms of WT1 Glomerulopathy

Asfahani, Rowan Isabel; (2019) Deciphering the Mechanisms of WT1 Glomerulopathy. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Wilms' tumour 1 (WT1) is a transcription factor encoding a zinc finger protein that controls podocyte differentiation and is highly expressed in mature podocytes. WT1 mutations can lead to renal failure due to glomerular scarring, the underlying mechanisms, of which, are poorly understood. This project explored the mechanisms of glomerulosclerosis by using a tamoxifen-inducible Cre-LoxP system to delete Wt1 in adult mice. Following the fourth day post-induction with Tamoxifen, podocyte apoptosis was evident and increased as the disease progressed, highlighting Wt1’s key role in mature podocyte survival. At disease onset, increased podocyte Notch1 transcript and its downstream targets, including Nrarp and Hey2 were observed. Decreased expression of podocyte FoxC2 transcript at the same time-point was noted, thereby supporting previous findings in lower vertebrates for a transcriptional relationship between Wt1/FoxC2/Notch in podocyte function. Podocyte Notch1 and Hes1 protein expression was observed in mutant mouse glomeruli at the onset of glomerulosclerosis. Induced podocyte Hes1 expression was associated with an upregulation of Snai1 and Slug transcripts, genes associated with epithelial to mesenchymal transition (EMT), thus proposing a role for Hes1 in mediating podocyte EMT. Moreover, early pharmacological inhibition of Notch, with gamma secretase inhibitors, ameliorated glomerulosclerosis and albuminuria. This data provides evidence that Wt1 deletion modulates podocyte Notch signalling in mature podocytes, leading to early events in WT1-related glomerulosclerosis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Deciphering the Mechanisms of WT1 Glomerulopathy
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/ 4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10074448
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