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Activation of podocyte Notch mediates early Wt1 glomerulopathy

Asfahani, R; Tahoun, MM; Miller-Hodges, EV; Bellerby, J; Virasami, AK; Sampson, RD; Moulding, D; ... Waters, AM; + view all (2018) Activation of podocyte Notch mediates early Wt1 glomerulopathy. Kidney International 10.1016/j.kint.2017.11.014. (In press). Green open access

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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.

Type: Article
Title: Activation of podocyte Notch mediates early Wt1 glomerulopathy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.kint.2017.11.014
Publisher version: http://doi.org/10.1016/j.kint.2017.11.014
Language: English
Additional information: Crown Copyright ª 2017, Published by Elsevier, Inc., on behalf of the International Society of Nephrology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: albuminuria; focal segmental glomerulosclerosis; nephrotic syndrome; podocyte
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 Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10042880
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