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

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 (? and ?) 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-?-catenin. This work clearly identifies GSK3 as a critical regulator of podocyte and hence kidney function.

SUBMITTER: Hurcombe JA

PROVIDER: S-EPMC6345761 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Hurcombe J A JA Hartley P P Lay A C AC Ni L L Bedford J J JJ Leader J P JP Singh S S Murphy A A Scudamore C L CL Marquez E E Barrington A F AF Pinto V V Marchetti M M Wong L-F LF Uney J J Saleem M A MA Mathieson P W PW Patel S S Walker R J RJ Woodgett J R JR Quaggin S E SE Welsh G I GI Coward R J M RJM

Nature communications 20190124 1

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 neonata ...[more]

PMID: 30679422

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Project description:Podocytes are crucial for the establishment of the blood-urine filtration barrier in the glomeruli of the kidney. These cells are mainly affected during glomerulopathies causing proteinuria and kidney function impairment. Ongoing podocyte injury leads to podocyte loss, finally followed by end-stage kidney disease. Podocytes display a predominant nuclear localization of YAP (Yes-associated protein), one effector protein of the Hippo pathway, which regulates the balance between proliferation, differentiation, and apoptosis in cells. Nuclear active YAP seems to be critical for podocyte survival in vivo and in vitro. We can show here that different treatments leading to sequestration of YAP into the cytoplasm in podocytes, like decreased rigidity of the substrate, incubation with dasatinib, or overexpression of Hippo pathway members result in the induction of apoptosis. A RNA sequencing analysis of large tumor suppressor kinase 2 (LATS2) overexpressing podocytes confirmed a significant upregulation of apoptotic genes. The downregulation of Hippo pathway components suggests a feedback mechanism in podocytes. Noteworthy was the regulation of genes involved in cell-cell junction, the composition of the extracellular space, and cell migration. This suggests an influence of Hippo pathway activity on podocyte integrity. As focal segmental glomerulopathy (FSGS) goes along with an activation of the Hippo pathway in podocytes, a comparison of our data with two independent studies of transcriptional regulation in human FSGS glomeruli obtained from the Nephroseq database was performed. This comparison affirmed a multitude of consistent transcriptional changes concerning the regulation of genes influencing apoptosis and the Hippo signaling pathway as well as cell junction formation and cell migration. The link between Hippo pathway activation in podocytes and the regulation of junction and migration processes in vivo might be a fundamental mechanism of glomerular sclerosis and loss of renal function.

Dataset Information

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

Publications

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

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