Podocyte GSK3α is important for autophagy and its loss detrimental for glomerular function

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 (a and beta). In the podocyte it has previously been reported that inhibition of the beta 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 GSK3 alpha is in these cells. We now show that GSK3 alpha is present and dynamically modulated in podocytes. When GSK3 alpha 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 GSK3 alpha causes cell death and impaired autophagic flux suggesting it is important for this key cellular process. Collectively this work shows that GSK3 alpha is important for podocyte health and that augmenting its function may be beneficial in treating glomerular disease.