ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-OR032

Promotion of β-Catenin/Foxo Protects against Kidney Fibrosis

Session Information

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
  • Rao, Padmashree, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia
  • Chen, Titi, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia
  • Yu, Hong, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia
  • Hu, Min, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia
  • Cao, Qi, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia
  • Wang, Yiping, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia
  • P'ng, Chow Heok, ICPMR, Westmead Hospital, Department of Tissue Pathology and Diagnostic Oncology, Westmead, New South Wales, Australia
  • Nankivell, Brian John, Westmead Hospital, Westmead, New South Wales, Australia
  • Lee, Vincent W.S., Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia
  • Alexander, Stephen I., Centre for Kidney Research, Children?s Hospital at Westmead., Westmead, New South Wales, Australia
  • Zheng, Guoping, Westmead Institute for Medical Research at University of Sydney, Westmead, New South Wales, Australia
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.