Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function

Jennifer A Hurcombe ,Vanda Pinto ,Shantanu Singh ,Lan Ni ,James B Uney ,Susan E Quaggin ,Cheryl L Scudamore ,Andrew J Murphy ,Moin A Saleem ,Peter W Mathieson ,M A Marchetti ,Eva Márquez ,Paul S Hartley ,Satish Patel ,Abigail C Lay ,James R Woodgett ,Jennifer J Bedford ,John P Leader ,Liang‐Fong Wong ,Alexandra F Barrington ,Gavin I Welsh ,Robert Walker ,Richard J M Coward

doi:10.1038/s41467-018-08235-1

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.

Highlights

Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death
Histological examination using light and transmission electron microscopy (TEM) revealed that glomerular and renal abnormalities were initially subtle in podGSK3DKO mice, but these rapidly progressed over the first 10 days of life to show glomerulosclerosis, multiple tubular protein casts and major disruption of the glomerular filtration barrier on TEM (Fig. 1e)
We examined the direct impact of lithium on nephrocyte function in Drosophila using an ex vivo culture system involving semi-intact fly preparations

Summary

Introduction

Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death. 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. Glycogen Synthase Kinase 3 (GSK3) is a multi-functional serine/threonine protein kinase that regulates several distinct biological pathways[8]. It was initially described as a component of glycogen metabolism and was later shown to be downstream of insulin signalling. GSK3 has two major biological actions; as a scaffolding protein and a kinase enzyme to catalyse a variety of downstream targets[10]

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Conclusion