Projects per year
Abstract
The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis.
Original language | English |
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Pages (from-to) | 903-920 |
Journal | Kidney International |
Volume | 93 |
Issue number | 4 |
Early online date | 2 Feb 2018 |
DOIs | |
Publication status | Published - 1 Apr 2018 |
Fingerprint
Dive into the research topics of 'Activation of podocyte Notch mediates early Wt1 glomerulopathy'. Together they form a unique fingerprint.Projects
- 5 Finished
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ISP 2017/22-Hohenstein Peter
Hohenstein, P. (Principal Investigator)
1/04/17 → 31/03/22
Project: Research
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CSF1R in homeostasis and immunity
Hume, D. (Principal Investigator), Hohenstein, P. (Co-investigator) & Mabbott, N. (Co-investigator)
1/05/15 → 31/12/18
Project: Research
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beta-catenin Ser45 in development and disease
Hohenstein, P. (Principal Investigator) & Wishart, T. (Co-investigator)
1/02/15 → 30/06/18
Project: Research
Profiles
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Eve Miller-Hodges
- Deanery of Clinical Sciences - Senior Clinical Lecturer in Inherited Metabolic Disorders
- Centre for Inflammation Research
- Centre for Cardiovascular Science
Person: Academic: Research Active