Abstract: FR-PO391
Modulation of GSK-3β Expression by AMPK Ameliorates Diabetic Kidney Injury by Promoting IR Phosphorylation Cascade
Session Information
- Diabetic Kidney Disease: Basic - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Zhang, Bo, The First Affiliated Hospital of Nanjing Medical University, Nanjing, JIANGSU , China
- Duan, Suyan, The First Affiliated Hospital of Nanjing Medical University, Nanjing, JIANGSU , China
- Yuan, Yanggang, The First Affiliated Hospital of Nanjing Medical University, Nanjing, JIANGSU , China
Background
Insulin resistance is a systemic disorder that affects many organs and insulin-regulated pathways. Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). It has recently been found that GSK-3β may play a role in the pathogenesis of diabetes and DN; however, the specific mechanism is still unknown.We aimed to investigate whether GSK-3β has a role in the amelioration of podocyte injury and insulin resistance,thus suppressing the progression of DN. Moreover, the molecular mechanisms responsible for the effects were examined.
Methods
Podocyte insulin responses were investigated with western blotting, cellular glucose uptake assays and fluorescent imaging of the insulin receptor signalling.Quantitative (q)RT-PCR was employed to investigate changes in mRNA. Cell viability and motility were detected by CCK-8 and wound healing assay. Db/db mice injected with different treatment were also generated. ELISA measurements were also used.
Results
Our results demonstrated that AMPK modulates podocyte IR level and enhances insulin-stimulated phosphorylation of PI3K/Akt cascades in high-glucose condition and diabetic db/db mice. Plus, AMPK prevented hyperglycemia-induced increase of GSK3β phosphorylation, ameliorated glucose uptake into podocytes, and impaired podocyte viability and motility.Moreover,treatments for modulation of key proteins in AMPK- PI3K/Akt -GSK3β signalling results in a reduction of proteinuria and significant improvement in renal function and pathological damage in db/db mice.
Conclusion
These findings evoke a novel therapeutic concept for DN, implying that the pharmacologic activation of AMPK might suppress the progression of DN and podocyte injury, also rescue podocyte insulin resistance. AMPK-PI3K/Akt- GSK3β pathway may be exploited as a therapeutic target for protection against podocyte injury and insulin resistance in DN.
Representative HE staining of diabetic kidney in each group