GSK3beta: a key regulator of glomerular podocyte injury in diabetic kidney disease

Abstract

Background: Emerging evidence suggests that glycogen synthase kinase (GSK3β), a critical transducer downstream of the insulin signaling pathway, acts as a convergent point for myriad pathways implicated in kidney injury, repair, and regeneration (1-3). However, its role in the pathogenesis of diabetic kidney disease remains highly controversial and was examined here (4, 5). Methods: Mouse podocytes were cultured under non-permissive conditions and exposed to a diabetic milieu containing high ambient glucose and insulin in the presence of proinflammatory stimulation. Cells were additionally subjected to GSK3β silencing, ectopic expression of a constitutively active GSK3β mutant (S9A), or treatment with tideglusib, a highly-selective small molecule inhibitor of GSK3β. Podocyte injury was assessed and signaling pathways examined. Results: Upon diabetic insult, podocytes demonstrated prominent signs of cytopathic changes, marked by loss of homeostatic marker proteins like synaptopodin, increased oxidative stress and apoptosis, and stress-induced premature senescence, as evidenced by increased staining for the acidic senescence-associated-β-galactosidase activity, amplified formation of γH2AX foci, and elevated expression of mediators of senescence signaling,