Abstract: FR-PO366
The Role of β-Catenin/Foxo in Renal Fibrosis
Session Information
- Mechanisms Associated with Kidney Fibrosis - I
November 03, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Chronic Kidney Disease (Non-Dialysis)
- 308 CKD: Mechanisms of Tubulointerstitial Fibrosis
Authors
- Rao, Padmashree, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
- Pang, Min, Shanxi Medical University, Taiyuan, China
- Qiao, Xi, Shanxi Medical University, Taiyuan, China
- Yu, Hong, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
- Wang, Hailong, Shanxi Medical University, Taiyuan, China
- Hu, Min, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
- Cao, Qi, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
- Wang, Yiping, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
- P'ng, Chow Heok, ICPMR, Westmead Hospital, Westmead, New South Wales, Australia
- Nankivell, Brian John, Westmead Hospital, Westmead, New South Wales, Australia
- Lee, Vincent W.S., Westmead Hospital, Westmead, New South Wales, Australia
- Alexander, Stephen I., Centre for Kidney Research, Children's Hospital at Westmead., Sydney, New South Wales, Australia
- Zheng, Guoping, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
- Harris, David C., Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
Background
TGF-β causes fibrosis by cross-talk with major profibrotic pathways. β-catenin is a common co-factor in different TGF-β signalling pathways. β-catenin binds to TCF to activate profibrotic genes, while β-catenin also binds to Foxo in competition with TCF. We propose that promoting β-catenin/Foxo will protect against β-catenin/TCF mediated profibrotic changes and kidney fibrosis.
Methods
Human kidney biopsies from kidney transplant and diabetic nephropathy patients were assessed for β-catenin/Foxo and β-catenin/TCF interactions in relation to kidney fibrosis. Mouse tubular epithelial C1.1 cells were treated with TGF-β1 with or without ICG-001 (5µM), an inhibitor of β-catenin/TCF. Foxo1 and TCF1 were knocked out by CRISPR/Cas9-mediated gene knockout. We evaluated kidney fibrosis in vivo in the unilateral ureteric obstruction (UUO) model. Profibrotic changes were examined by Western blot and immunofluorescence. Duolink - Proximity Ligation Assay (PLA) and co-immunoprecipitation assays (co-IP) were used to examine β-catenin/Foxo and β-catenin/TCF interactions.
Results
PLA of human kidney biopsies showed that β-catenin/Foxo correlated negatively (r=-0.785) whilst β-catenin/TCF correlated positively (r=0.679) with kidney fibrosis score (P<0.01). co-IP and PLA showed that ICG-001 promoted β-catenin/Foxo interaction by inhibiting β-catenin/TCF binding in TGF-β1-treated C1.1 cells. TGF-β1-induced β-catenin/TCF activity and expression of fibrotic genes (vimentin, N-cadherin, collagen I, III & IV) were reduced by ICG-001 and TCF1 knockout, while Foxo1 knockout prevented the reduction of the fibrotic gene expression. Kidney fibrosis was significantly reduced in UUO mice treated with TGF-β1 and ICG-001, which redirected TGF-β1 signalling from β-catenin/TCF to β-catenin/Foxo1 as shown by PLA.
Conclusion
These results indicate that β-catenin/Foxo plays a protective role against TGF-β’s profibrotic activity by inhibiting β-catenin/TCF interaction and thereby preventing kidney fibrosis.
Funding
- Government Support - Non-U.S.