Activation of Glycogen Synthase Kinase 3β Ameliorates Diabetes-induced Kidney Injury

Abstract

Background: High glucose-induced matrix protein synthesis in renal cells requires glycogen synthase kinase 3␤ (GSK3␤) inactivation. Results: Sodium nitroprusside (SNP) activated GSK3␤ and inhibited diabetes-induced kidney hypertrophy, matrix deposition, and albuminuria in mice without changing blood glucose. Conclusion: Activation of GSK3␤ by SNP ameliorates diabetic kidney injury. Significance: GSK3␤ may be a novel target for intervention in diabetic kidney disease.Increase in protein synthesis contributes to kidney hypertrophy and matrix protein accumulation in diabetes. We have previously shown that high glucose-induced matrix protein synthesis is associated with inactivation of glycogen synthase kinase 3␤ (GSK3␤) in renal cells and in the kidneys of diabetic mice. We tested whether activation of GSK3␤ by sodium nitroprusside (SNP) mitigates kidney injury in diabetes. Studies in kidneyproximal tubular epithelial cells showed that SNP abrogated high glucose-induced laminin increment by stimulating GSK3␤ and inhibiting Akt, mTORC1, and events in mRNA translation regulated by mTORC1 and ERK. NONOate, an NO donor, also activated GSK3␤, indicating that NO may mediate SNP stimulation of GSK3␤. SNP administered for 3 weeks to mice with streptozotocin-induced type 1 diabetes ameliorated kidney hypertrophy, accumulation of matrix proteins, and albuminuria without changing blood glucose levels. Signaling studies showed that diabetes caused inactivation of GSK3␤ by activation of Src, Pyk2, Akt, and ERK; GSK3␤ inhibition activated mTORC1 and downstream events in mRNA translation in the kidney cortex. These reactions were abrogated by SNP. We conclude that activation of GSK3␤ by SNP ameliorates kidney injury induced by diabetes.Diabetes is the major cause of end stage renal disease (1, 2). Diabetic kidney disease is characterized by excessive deposition of extracellular matrix in the form of thickening of glomerular and tubular basement membranes and increased amounts of mesangial matrix (glomerulosclerosis) and tubulo-interstitial fibrosis (3). We have previously reported that high glucose and high insulin, conditions associated with type 2 diabetes, increased protein synthesis, including matrix proteins in the renal proximal tubular epithelial (MCT) 3 cells (4). These changes were associated with inactivation of glycogen synthase kinase 3␤ (GSK3␤), a ubiquitously expressed and constitutively active serine/threonine kinase (5). GSK3␤ regulates a variety of cellular processes, including glycogen metabolism (6), gene transcription (7), apoptosis (8), and microtubule stability (9, 10); our studies have shown that it serves as a constitutive inhibitor of protein synthesis in renal epithelial cells (5). Akt promotes protein synthesis by phosphorylating GSK3␤ at Ser-9, thereby inhibiting its activity (11,12). GSK3␤ activity can also be regulated by 14). GSK3␤ regulates the activity of a broad range of substrates by phosphorylation (e.g. glucose metabolism by phosphorylation and inactivation of glycogen synthase (15) and protei...

Glycogen synthase kinase-3β is required for epithelial-mesenchymal transition and barrier dysfunction in mouse podocytes under high glucose conditions

“…These results implied that GSK-3β may be involved in DN. However, Mariappan et al (28) determined that the activation of GSK3β by sodium nitroprusside (SNP) reduced the HG-induced laminin increase (in contrast to the present study), an important characteristic of DN progression in kidney-proximal tubular epithelial cells. In addition, diabetes led to the inactivation of GSK3β by activation of the Src proto-oncogene, pyruvate kinase 2, protein kinase B and extracellular signal-related kinase.…”

“…In addition, diabetes led to the inactivation of GSK3β by activation of the Src proto-oncogene, pyruvate kinase 2, protein kinase B and extracellular signal-related kinase. Furthermore, GSK3β activation by SNP mitigated kidney injury induced by diabetes in vivo (28), indicating that GSK3β may suppress the progress of DN. To confirm the importance of GSK-3β in HG-induced EMT and barrier dysfunction in podocytes, GSK-3 β siRNA was transfected in podocytes in order to downregulate GSK-3β expression.…”

Rescue therapy with Tanshinone IIA hinders transition of acute kidney injury to chronic kidney disease via targeting GSK3β

“…To determine if inhibition of GSK3β possibly represents a key mechanism conveying the beneficial activity of Tanshinone IIA after AKI, additional mice received Tanshinone IIA therapy in the presence of daily treatment with vehicle or sodium nitroprusside, a GSK3β activator48, starting 1 day or 5 days after folic acid injury. Kidney specimens were procured 7 days after folic acid injury for immunoblot analysis (Fig.…”

Renoprotective effects of emodin against diabetic nephropathy in rat models are mediated via PI3K/Akt/GSK‑3β and Bax/caspase‑3 signaling pathways

“…Among the factors associated with the insulin signal transduction pathway, GSK-3β has received considerable attention because of its multiple substrates and broad impact (29). For example, insulin receptor substrate-1 (IRS-1) results in a reduction in insulin receptor signaling following phosphorylation by GSK-3β (30).…”