Kidney Week

Abstract: FR-OR032

Promotion of β-Catenin/Foxo Protects against Kidney Fibrosis

Session Information

• Cellular Crosstalk in Glomerular Diseases
  October 26, 2018 | Location: 25A, San Diego Convention Center
  Abstract Time: 05:18 PM - 05:30 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Harris, David C., Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia

David C. Harris, MD, MBBS

• Rao, Padmashree, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia

Padmashree Rao,

• Chen, Titi, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia

Titi Chen,

• Yu, Hong, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia

Hong Yu,

• Hu, Min, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia

Min Hu,

• Cao, Qi, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia

Qi Cao,

• Wang, Yiping, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia

Yiping Wang,

• P'ng, Chow Heok, ICPMR, Westmead Hospital, Department of Tissue Pathology and Diagnostic Oncology, Westmead, New South Wales, Australia

Chow Heok P'ng,

• Nankivell, Brian John, Westmead Hospital, Westmead, New South Wales, Australia

Brian John Nankivell,

• Lee, Vincent W.S., Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia

Vincent W.S. Lee,

• Alexander, Stephen I., Centre for Kidney Research, Children?s Hospital at Westmead., Westmead, New South Wales, Australia

Stephen I. Alexander,

• Zheng, Guoping, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia

Guoping Zheng,

Background

Transforming growth factor β (TGF-β) is the key cytokine in the development of fibrosis. The conflicting roles of TGF-β (profibrotic versus anti-inflammatory) create a dilemma in the treatment of kidney fibrosis. β-catenin/TCF is central to various TGF-β’s profibrotic signaling pathways in fibrosis. β-catenin also binds to Foxo in competition with TCF and leads to cell cycle arrest, promoting cell survival under oxidative stress. We propose that promoting β-catenin/Foxo will protect against β-catenin/TCF-mediated profibrotic changes and kidney fibrosis.

Methods

Kidney biopsies of patients with chronic kidney disease (CKD) or a kidney transplant were assessed by Proximity Ligation Assay (PLA) for β-catenin/Foxo and β-catenin/TCF interactions in relation to kidney fibrosis. Murine proximal tubular epithelial C1.1 cells were treated with TGF-β1 (3ng/ml) with or without ICG-001 (5µM), which inhibits β-catenin/TCF. CRISPR/Cas9 gene technology was used to knockout Foxo1 or TCF1. We also evaluated kidney fibrosis in murine unilateral ureteric obstruction (UUO). β-catenin/Foxo and β-catenin/TCF interactions were examined by co-immunoprecipitation (co-IP) and PLA. Profibrotic gene expressions were examined by western blot and immunofluorescence.

Results

PLA of CKD and kidney transplant patient biopsies showed that β-catenin/Foxo correlated negatively (r=-0.7405, P<0.001) and β-catenin/TCF positively (r=0.8061, P<0.001) with kidney fibrosis. TGF-β1 and ICG-001 treatment in C1.1 cells protected against TGF-β1-induced profibrotic gene expression while the protection was absent in Foxo1 KO C1.1 cells. Combined treatment with TGF-β1 and ICG-001 in C1.1 cells showed direct evidence for the promotion of β-catenin/Foxo by PLA and co-IP. UUO mice treated with TGF-β1 and ICG-001 had significantly reduced kidney fibrosis, via promotion of β-catenin/Foxo interaction as shown by PLA.

Conclusion

β-catenin/Foxo protects against TGF-β’s profibrotic activity and thereby prevents kidney fibrosis.

Funding

• Government Support - Non-U.S.