β-CATENIN/FOXO PROTECTS AGAINST KIDNEY FIBROSIS

P RAO 1, M PANG 1,2, X QIAO 1,2, H YU 1, H WANG 1,2, M HU1, Q CAO 1, Y WANG 1, G ZHANG 3,  Y WANG 3, CH P’NG 4, B NANKIVELL4, VW LEE 1, S ALEXANDER 3, G ZHENG 1, D HARRIS 1

1University of Sydney at Westmead Institute for Medical Research, Westmead, New South Wales; 2Shanxi Medical University, Taiyuan, China; 3Children’s Hospital at Westmead, Westmead, New South Wales; 4Westmead Hospital, New South Wales

Aim: To examine the role of β-catenin/Foxo in kidney fibrosis.

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/TCF is known 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 patients with a kidney transplant and diabetes 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 unilateral ureteric obstruction (UUO). Profibrotic changes were examined by Western blot and immunofluorescence analysis of profibrotic proteins. 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=-0.877) whilst β-catenin/TCF correlated positively (r=0.926) with kidney fibrosis (P<0.01). ICG-001 promoted β-catenin/Foxo interaction by inhibiting β-catenin/TCF binding in TGF-β1-treated C1.1 cells, as shown by co-IP and PLA. 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 with TGF-β1 and ICG-001 treatment, which redirected TGF-β1 signalling from β-catenin/TCF to β-catenin/Foxo1 as shown by PLA.

Conclusions: 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.

About ANZSN

The ASM is hosted by Australian and New Zealand Society of Nephrology.

The aims of the Society are to promote and support the study of the kidney and urinary tract in health and disease, and to ensure the highest professional standards for the practice of nephrology in Australia and New Zealand.

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