Abstract
Podocytes are key cells in maintaining the integrity of the glomerular filtration barrier and preventing albuminuria. Glycogen synthase kinase 3 (GSK3) is a multi‐functional serine/threonine kinase existing as two distinct but related isoforms (α and β). In the podocyte it has previously been reported that inhibition of the β isoform is beneficial in attenuating a variety of glomerular disease models but loss of both isoforms is catastrophic. However, it is not known what the role of GSK3α is in these cells. We now show that GSK3α is present and dynamically modulated in podocytes. When GSK3α is transgenically knocked down specifically in the podocytes of mice it causes mild but significant albuminuria by 6 weeks of life. Its loss also does not protect in models of diabetic or Adriamycin‐induced nephropathy. In vitro deletion of podocyte GSK3α causes cell death and impaired autophagic flux suggesting it is important for this key cellular process. Collectively this work shows that GSK3α is important for podocyte health and that augmenting its function may be beneficial in treating glomerular disease.
Highlights
The podocyte is critical to the proper functioning of the mammalian glomerular filtration barrier and the prevention of albuminuria, a hallmark of kidney disease
There is evidence that GSK3α and β are not entirely redundant and have different functions: GSK3β null mice die during late embryogenesis as a result of impaired NFκB signaling and cardiac defects 3,4 whereas whole body GSK3α knockout mice are Abbreviations: AKT, protein kinase B; BSA, bovine serum albumin; ELISA, enzyme‐linked immunosorbent assay; FBS, fetal bovine serum; FSGS, focal segmental glomerulosclerosis; Glycogen synthase kinase 3 (GSK3), glycogen synthase kinase 3; KO, knockout; MAPK, mitogen‐activated protein kinase; PAS, periodic acid Schiff; PBS, phosphate buffered saline; PCR, polymerase chain reaction; Platelet‐derived growth factor (PDGF), platelet‐derived growth factor; Platelet endothelial cell adhesion molecule‐1 (PECAM)‐1, platelet endothelial cell adhesion molecule‐1; STZ, streptozotocin; TBS‐T, tris‐buffered saline‐tween 20; Urinary albumin creatinine ratio (uACR), urinary albumin creatinine ratio; WT, wild‐type; WT‐1, Wilm's tumor protein
We show here that in contrast to previous research indicating that podocyte‐specific genetic knockout of GSK3β has a beneficial effect in models of kidney disease; podocyte ablation of GSK3α is not protective
Summary
The podocyte is critical to the proper functioning of the mammalian glomerular filtration barrier and the prevention of albuminuria, a hallmark of kidney disease. We showed that prolonged pharmacological inhibition of GSK3 in rats using lithium caused significant proteinuria with evidence of focal segmental glomerulosclerosis (FSGS).[10] This is consistent with reports of FSGS and renal failure in patients on long‐term lithium therapy for conditions such as bipolar disorder.[11,12] In contrast, a number of recent studies suggest that partial pharmacological inhibition of GSK3 as well as specific genetic knockout of the β isoform in podocytes can be beneficial in a number of experimental glomerular disease models including diabetic nephropathy, lupus nephritis and Adriamycin nephropathy.[13,14,15,16,17] the role of podocyte GSK3α has received little consideration and it is not known whether this isoform has a specific role in podocyte homeostasis or if its loss can have a podocyte protective effect. We found that loss of podocyte GSK3α is mildly detrimental and reveal a role for this isoform in maintaining podocyte autophagic flux
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