β-CATENIN/FOXO AMELIORATES KIDNEY FIBROSIS

P RAO1, M PANG1,2, X QIAO1,2, H YU1, T CHEN1, H WANG1,2,  M HU1, Q CAO1,  Y WANG1,  G ZHANG3, Y WANG3, C P’NG4, B Nankivell4, V Lee1, S Alexander3, G Zheng1, D Harris1
1University of Sydney at Westmead Institute for Medical Research, Westmead, Australia, 2Shanxi Medical University, , China, 3Children’s Hospital at Westmead, Westmead, Australia, 4Westmead Hospital, Westmead, Australia

Aim: To examine the role of β-catenin/Foxo in kidney fibrosis.
Background: The conflicting effects of TGF-β (profibrotic versus anti-inflammatory) have caused a major challenge in the treatment of kidney fibrosis. β-catenin/TCF is central to all TGF-β’s profibrotic signaling pathways and activates profibrotic genes. β-catenin also binds to Foxo in competition with TCF and promotes 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. Mouse tubular epithelial C1.1 cells were treated with TGF-β1 (3ng/ml) with or without ICG-001 (5µM), which inhibits β-catenin/TCF. Foxo1 and TCF1 were knocked out by CRISPR/Cas9-mediated gene knockout. We also evaluated kidney fibrosis in murine unilateral ureteric obstruction (UUO). β-catenin/Foxo and β-catenin/TCF interactions were examined by co-immunoprecipitation assays (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. Combined treatment with TGF-β1 and ICG-001 protected against TGF-β1-induced profibrotic gene expression while the protection was not seen in Foxo1 KO C1.1 cells. PLA and co-IP showed direct evidence for the promotion of β-catenin/Foxo with TGF-β1 and ICG-001 in C1.1 cells. 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.
Conclusions: These results indicate that β-catenin/Foxo plays a protective role against TGF-β’s profibrotic activity and thereby prevents kidney fibrosis.


Biography:
Padmashree Rao is the student of the University of Sydney at Westmead Institute for Medical Research. Her research has been focused on kidney fibrosis. TGF-beta, a cytokine causing kidney fibrosis, also exhibits anti-inflammatory and wound healing effects. Her project aims to prove that targeting beta-catenin/Foxo will prevent beta-catenin/TCF-mediated fibrosis and may be used as a novel target for the treatment of kidney fibrosis.

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