Abstract: TH-PO901
Therapeutic Targeting of GSK3β Rectifies Profibrogenic Plasticity of Renal Tubular Epithelial Cells in Progressive CKD
Session Information
- Molecular Mechanisms of CKD - I
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Chen, Bohan, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Wang, Pei, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Dworkin, Lance D., University of Toledo Medical Center, Toledo, Ohio, United States
- Liu, Zhangsuo, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gong, Rujun, University of Toledo Medical Center, Toledo, Ohio, United States
Background
Renal tubular cells play a key role in chronic kidney injury. After a prolonged persistent injury beyond self-healing capacity, renal tubular cells will resort to maladaptive plasticity and undergo dedifferentiation, growth arrest and convertion to profibrogenic phenotypes that ultimately lead to renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in maladaptive renal tubular cell plasticity is unknown and was explored here.
Methods
In cultured renal tubular cells expressing diverse GSK3β mutants or treated with GSK3β inhibitors, TGFβ1-induced phenotypic changes were evaluated. In mice with tubular specific knockout of GSK3β or in mice treated with microdose lithium folic acid-induced chronic kidney injury was examined.
Results
TGFβ1 treatment triggered renal tubular cell dedifferentiation, marked by conversion from cuboidal to dispersed spindle shape, loss of cell tight junction molecules like E-cadherin and ZO-1, and de novo expression of vimentin. In addition, growth inhibition was noted as shown by cell cycle arrest at G2/M phase. Moreover, increased extracellular matrix proteins like collagen I and fibronectin, as well as overproduction of profibrotic cytokines, such as PAI-1 and CTGF, was evident after TGFβ1 exposure. All these profibrogenic phenotypes were reinforced in cells expressing the constitutively active mutant of GSK3β, but largely abolished by ectopic expression of a dominant negative mutant or by GSK3β inhibitors. Mechanistically, GSK3β blockade potentiated CREB activity and subsequently antagonized the TGFβ1/Smad signaling, which drives tubular cell profibrogenic plasticity. Moreover, structural rather than transcriptional β-catenin was up-regulated after GSK3β inhibition, denoting a strengthened cell tight junction. So did cyclin D1, an essential element for cell cycle progression. In vivo, in folic acid-injured mice, tubular cell dedifferentiation, G2/M arrestrenal and PAI-1 and CTGF expression were all mitigated by GSK3β gene ablation or by microdose lithium, a standard GSK3b inhibitor, concomitant with attenuated tubular atrophy and renal fibrosis.
Conclusion
GSK3β is likely a pragmatic therapeutic target for correcting profibrogenic plasticity of renal tubular cells in CKD to improve renal fibrosis.