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Nat Commun. 2019 Jan 24;10(1):403. doi: 10.1038/s41467-018-08235-1.

Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function.

Author information

1
Bristol Renal, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
2
Bournemouth University, Bournemouth, BH12 5BB, UK.
3
Dunedin School of Medicine, University of Otago, Dunedin, 9016, New Zealand.
4
Department of Pathology, Southern General Hospital, Glasgow, G51 4TF, UK.
5
Mary Lyon Centre, MRC Harwell, Didcot, Oxford, OX11 0RD, UK.
6
Translational Health Sciences, University of Bristol, Bristol, BS2 8DZ, UK.
7
The University of Hong Kong, Pokfulam, Hong Kong.
8
Lunenfeld-Tanenbaum Research Institute, Sinai Health System & University of Toronto, Toronto, M5G 1X5, Canada.
9
Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
10
Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, 60611, IL, USA.
11
Bristol Renal, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK. Richard.Coward@bristol.ac.uk.

Abstract

Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death. The key cell that prevents albuminuria is the terminally differentiated glomerular podocyte. Here we report the evolutionary importance of the enzyme Glycogen Synthase Kinase 3 (GSK3) for maintaining podocyte function in mice and the equivalent nephrocyte cell in Drosophila. Developmental deletion of both GSK3 isoforms (α and β) in murine podocytes causes late neonatal death associated with massive albuminuria and renal failure. Similarly, silencing GSK3 in nephrocytes is developmentally lethal for this cell. Mature genetic or pharmacological podocyte/nephrocyte GSK3 inhibition is also detrimental; producing albuminuric kidney disease in mice and nephrocyte depletion in Drosophila. Mechanistically, GSK3 loss causes differentiated podocytes to re-enter the cell cycle and undergo mitotic catastrophe, modulated via the Hippo pathway but independent of Wnt-β-catenin. This work clearly identifies GSK3 as a critical regulator of podocyte and hence kidney function.

PMID:
30679422
PMCID:
PMC6345761
DOI:
10.1038/s41467-018-08235-1
[Indexed for MEDLINE]
Free PMC Article

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