Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.779422
Title: Deciphering the mechanisms of WT1 glomerulopathy
Author: Asfahani, Rowan Isabel
ISNI:       0000 0004 7965 118X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.779422  DOI: Not available
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