Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function

J. A. Hurcombe, P. Hartley, A. C. Lay, L. Ni, J. J. Bedford, J. P. Leader, S. Singh, A. Murphy, C. L. Scudamore, E. Marquez, A. F. Barrington, V. Pinto, M. Marchetti, L.-F. Wong, J. Uney, M. A. Saleem, P. W. Mathieson, S. Patel, R. J. Walker, J. R. Woodgett, S. E. Quaggin, G. I. Welsh and R. J. M. Coward ()
Additional contact information
J. A. Hurcombe: University of Bristol
P. Hartley: Bournemouth University
A. C. Lay: University of Bristol
L. Ni: University of Bristol
J. J. Bedford: University of Otago
J. P. Leader: University of Otago
S. Singh: University of Bristol
A. Murphy: Southern General Hospital
C. L. Scudamore: Mary Lyon Centre, MRC Harwell, Didcot
E. Marquez: University of Bristol
A. F. Barrington: University of Bristol
V. Pinto: University of Bristol
M. Marchetti: University of Bristol
L.-F. Wong: University of Bristol
J. Uney: University of Bristol
M. A. Saleem: University of Bristol
P. W. Mathieson: University of Bristol
S. Patel: Sinai Health System & University of Toronto
R. J. Walker: University of Otago
J. R. Woodgett: Sinai Health System & University of Toronto
S. E. Quaggin: Northwestern University Feinberg School of Medicine
G. I. Welsh: University of Bristol
R. J. M. Coward: University of Bristol

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08235-1

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