Promotion of β-catenin/Foxo1 signaling ameliorates renal interstitial fibrosis

Transforming growth factor beta (TGF-beta) is the key cytokine involved in causing fibrosis through cross-talk with major profibrotic pathways. However, inhibition of TGF-beta to prevent fibrosis would also abrogate its anti-inflammatory and wound-healing effects. beta-catenin is a common co-factor in most TGF-beta signaling pathways. beta-catenin binds to T-cell factor (TCF) to activate profibrotic genes and binds to Forkhead box O (Foxo) to promote cell survival under oxidative stress. Using a proximity ligation assay in human kidney biopsies, we found that beta-catenin/Foxo interactions were higher in kidney with little fibrosis, whereas beta-catenin/TCF interactions were upregulated in the kidney of patients with fibrosis. We hypothesised that beta-catenin/Foxo is protective against kidney fibrosis. We found that Foxo1 protected against rhTGF-beta 1-induced profibrotic protein expression using a CRISPR/cas9 knockout of Foxo1 or TCF1 in murine kidney tubular epithelial C1.1 cells. Co-administration of TGF-beta with a small molecule inhibitor of beta-catenin/TCF (ICG-001), protected against kidney fibrosis in unilateral ureteral obstruction. Collectively, our human, animal and in vitro findings suggest beta-catenin/Foxo as a therapeutic target in kidney fibrosis.