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; R. J.M. Coward

doi:10.1038/s41467-018-08235-1

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. WoodgettS. E. Quaggin, G. I. Welsh, R. J.M. Coward^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

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.

Original language	English (US)
Article number	403
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08235-1
State	Published - Dec 1 2019

Funding

This work was funded by Kidney Research UK, the Medical Research Council, which funds RJMC with a Senior Research Fellowship (MR/K010492/1), European Renal Association-European Dialysis Transplantation Association (ERA-EDTA), Canadian Institutes of Health Research and the National Institute of Health. Latterly it was supported by funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115974. This Joint Undertaking receives support from the European Union\u2019s Horizon 2020 research and innovation programme and EFPIA with JDRF.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hurcombe, J. A., Hartley, P., Lay, A. C., Ni, L., Bedford, J. J., Leader, J. P., Singh, S., Murphy, A., Scudamore, C. L., Marquez, E., Barrington, A. F., Pinto, V., Marchetti, M., Wong, L. F., Uney, J., Saleem, M. A., Mathieson, P. W., Patel, S., Walker, R. J., ... Coward, R. J. M. (2019). Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function. Nature communications, 10(1), Article 403. https://doi.org/10.1038/s41467-018-08235-1

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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.",

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Hurcombe, JA, Hartley, P, Lay, AC, Ni, L, Bedford, JJ, Leader, JP, Singh, S, Murphy, A, Scudamore, CL, Marquez, E, Barrington, AF, Pinto, V, Marchetti, M, Wong, LF, Uney, J, Saleem, MA, Mathieson, PW, Patel, S, Walker, RJ, Woodgett, JR, Quaggin, SE, Welsh, GI & Coward, RJM 2019, 'Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function', Nature communications, vol. 10, no. 1, 403. https://doi.org/10.1038/s41467-018-08235-1

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AU - Hurcombe, J. A.

AU - Hartley, P.

AU - Lay, A. C.

AU - Ni, L.

AU - Bedford, J. J.

AU - Leader, J. P.

AU - Singh, S.

AU - Murphy, A.

AU - Scudamore, C. L.

AU - Marquez, E.

AU - Barrington, A. F.

AU - Pinto, V.

AU - Marchetti, M.

AU - Wong, L. F.

AU - Uney, J.

AU - Saleem, M. A.

AU - Mathieson, P. W.

AU - Patel, S.

AU - Walker, R. J.

AU - Woodgett, J. R.

AU - Quaggin, S. E.

AU - Welsh, G. I.

AU - Coward, R. J.M.

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N2 - 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.

AB - 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.

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Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function

Abstract

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ASJC Scopus subject areas

UN SDGs

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