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Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function

Research output: Contribution to journalArticle

Original languageEnglish
Article number403
Number of pages17
JournalNature Communications
Volume10
Issue number1
Early online date24 Jan 2019
DOIs
DateAccepted/In press - 23 Dec 2018
DateE-pub ahead of print - 24 Jan 2019
DatePublished (current) - 2019

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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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Springer Nature at https://www.nature.com/articles/s41467-018-08235-1 . Please refer to any applicable terms of use of the publisher.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Springer Nature at https://www.nature.com/articles/s41467-018-08235-1 . Please refer to any applicable terms of use of the publisher.

    Final published version, 193 MB, PDF document

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