Role of GSK3beta in diabetic kidney disease

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ABSTRACT Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease with no definitive therapy yet available. Emerging evidence suggests that defective insulin signaling in podocytes plays a key role in the pathogenesis of DKD. In addition, the “final common molecular pathway” for glomerular degeneration contributes to DKD, involving oxidative damage and stress-induced premature senescence. Glycogen synthase kinase (GSK)3 is a critical transducer of insulin signaling, and also acts as a convergent point for myriad pathways implicated in organ injury, repair, and regeneration. In renal glomeruli, GSK3β rather than the α isoform is predominantly expressed and enriched in podocytes. Our latest studies demonstrated that GSK3β is hyperactive in glomerular podocytes in clinical and experimental DKD, correlating with the severity and progression of DKD and associated with accelerated podocyte senescence. However, the role of GSK3β in diabetic nephropathy (DN) is extremely controversial based on very few studies solely relying on chemical inhibitors or activators with specificity concerns. Preliminary data revealed that GSK3β catalyzes phosphorylation of p53 and p16INK4A, pivotal mediators of senescence signaling in podocytes, and that GSK3β-regulated Keap1-independent Nrf2 antioxidant defense is a new actionable target for podocyte protection. Furthermore, GSK3β inhibition promotes the expression and activity of retinoic acid (RA) receptor (RAR)α, a key transcription factor driving podocyte differentiation and repair. Building logically on previous work, this project aims to conclusively define the exact role of GSK3β in DN and test a novel hypothesis that targeting GSK3β in podocytes mimics or sensitizes insulin signaling, reinforces Nrf2 antioxidant response, mitigates senescence, and synergizes with RARα signaling, resulting in a beneficial effect in DN. Aim 1 will define the molecular mechanism underlying GSK3β regulation of diabetic podocyte injury. GSK3β activity will be manipulated in podocytes exposed to the diabetic milieu and its role in insulin signaling, Nrf2 response and accelerated podocyte senescence will be defined. Aim 2 will examine the role of podocyte-specific GSK3β in DN. In mice with type 1 DN elicited by streptozotocin plus uninephrectomy, or in db/db mice with type 2 DN, GSK3β activity will be promoted by GSK3β knockin or podocyte-specific GSK3β hyperactivity, or inhibited by inducible conditional knockout (icKO) of GSK3β. The rescue efficacy of small molecule inhibitors of GSK3β, including microdose lithium and tideglusib, on established DN will be further evaluated. Aim 3 will test the synergistic effect of GSK3β inhibition plus RA on DN. Mice with icKO of GSK3β and RARα in podocytes will be employed to determine if RARα contributes to GSK3β regulation of DN. The role of GSK3β in regulating RARα activity will be defined using podocytes with differing GSK3β activity and validated in GSK3βicKO mice with type 1 or 2 DN. The synergistic effect of RA plus GSK3β inhibitors on DN will be tested. Collectively, these studies will provide a mechanistic view of the role of GSK3β in the pathogenesis of DN and pave the way for trials of existing or novel medications with GSK3β inhibitory activities to treat DKD in men.