A schematic diagram illustrates the multifaceted role of the redox-sensitive GSK3β in podocyte injury upon type 2 diabetic insult and the protective effect of targeting GSK3β.GSK3β is predominantly expressed in glomeruli and highly enriched in glomerular podocytes. The present study demonstrated that GSK3β is hyperactive in podocytes in type 2 diabetic kidney disease, recapitulated in vitro by a type 2 diabetic milieu consisting of high ambient insulin and glucose as well as microinflammation resembled by a low-level inflammatory background of TNF-α and IL-6. As a redox-sensitive kinase, GSK3β hyperactivity in podocytes may be primarily caused by diabetes-associated oxidative stress. Subsequently, GSK3β hyperactivity diminishes Nrf2 nuclear accumulation in podocytes, and thereby mitigates the expression of a number of enzymatic antioxidants, including HO-1 and NQO1, resulting in overproduction of reactive oxygen species (ROS), more specifically H2O2. This will further promote GSK3β hyperactivity and thus form a vicious cycle. Meanwhile, augmented oxidative stress will cause DNA damage and protein tyrosine nitration and thereby activate the cellular senescence signaling and worsen podocyte senescence, though GSK3β per se has been shown to directly drive podocyte senescence signaling. On the other side, as a key transducer of the insulin signaling pathway, GSK3β is able to regulate IRS-1 phosphorylation at Serine 332, which negatively regulates IRS-1 activity. GSK3β hyperactivity causes IRS-1 hyperphosphorylation and thereby de-sensitizes insulin signaling, resulting in reduced inhibitory inhibition of GSK3β and another vicious cycle of GSK3β hyperactivity. De-sensitized insulin signaling also affects the translocation of GLUT4 to the plasma membrane and glucose uptake in podocytes, leading to glucose metabolic reprogramming. All the above pathogenic pathways are involved in diabetic podocyte injury in type 2 diabetes and could be intercepted by genetic targeting of GSK3β via RNAi or pharmacological targeting via using small molecule inhibitors, such as tideglusib (TDG). Abbreviations: ARE, antioxidant responsive element; GSVs, GLUT storage vesicles
