Abstract: SA-PO071
GSK3-Beta Inhibits Tubular Regeneration in AKI by a FoxM1-Dependent Mechanism
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Jamadar, Abeda, University of Kansas Medical Center, Kansas City, Kansas, United States
- Sinha, Sonali, University of Kansas Medical Center, Kansas City, Kansas, United States
- Dwivedi, Nidhi, University of Kansas Medical Center, Kansas City, Kansas, United States
- Rao, Reena, University of Kansas Medical Center, Kansas City, Kansas, United States
Background
Acute kidney injury (AKI) is characterized by injury to the tubular epithelium. Although renal tubules are capable of regeneration, inadequate repair and fibrosis can lead to chronic kidney diease. FoxM1 is a forkhead box family member transcription factor which regulates cell division, survival and oxidative stress. FoxM1 is also a substrate for glycogen synthase kinase 3beta (GSK3-beta), a known inhibitor of renal tubular regeneration in AKI. The current study tested the hypothesis that GSK3-beta suppresses tubular repair after AKI by inhibiting FoxM1.
Methods
To determine the role of FoxM1 in tubular repair, the effect of FoxM1 inhibition was examined in renal ischemia/reperfusion (I/R) induced AKI in C57BL/6J mice and HK2 proximal tubular cells in vitro.
Results
Renal FoxM1 expression increased after I/R induced AKI in mice and was accompanied by increased cell proliferation. Treatment with Thiostrepton, a FoxM1 inhibitor reduced renal tubular cell proliferation and kidney tubular repair. To test if GSK3-beta regulates FoxM1, the effect of FoxM1 inhibitor on tubule-specific GSK3-beta knockout mouse was determined. In GSK3-beta knockout mice, FoxM1 expression, cell proliferation and tubular repair were significantly high, leading to improved renal function. Significant increase in p21, a cell cycle inhibitor and reduction in pro-proliferative factors were found in cells and kidneys where GSK3-beta was inhibited. Thiostrepton treatment abolished the improved tubular repair in GSK3-beta knockout mice.
Conclusion
These studies demonstrate that FoxM1 is an important factor for renal tubular regeneration following AKI, and that GSK3-beta suppresses tubular repair by inhibiting FoxM1
Funding
- NIDDK Support