Abstract
Transforming growth factor β (TGF-β) is the key cytokine involved in causing fibrosis through cross-talk with major profibrotic pathways. However, inhibition of TGF-β to prevent fibrosis would also abrogate its anti-inflammatory and wound-healing effects. β-catenin is a common co-factor in most TGF-β signaling pathways. β-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 β-catenin/Foxo interactions were higher in kidney with little fibrosis, whereas β-catenin/TCF interactions were upregulated in the kidney of patients with fibrosis. We hypothesised that β-catenin/Foxo is protective against kidney fibrosis. We found that Foxo1 protected against rhTGF-β1-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-β with a small molecule inhibitor of β-catenin/TCF (ICG-001), protected against kidney fibrosis in unilateral ureteral obstruction. Collectively, our human, animal and in vitro findings suggest β-catenin/Foxo as a therapeutic target in kidney fibrosis.
Highlights
Kidney fibrosis is characterized by over-production and deposition of extracellular matrix and is considered to be a crucial factor in driving chronic kidney disease (CKD) towards kidney failure [1, 2]
We showed that the binding of β-catenin to Forkhead box O (Foxo) protected against Transforming growth factor β (TGF-β)-induced profibrotic effects and ameliorated kidney fibrosis
To assess the relevance of this to humans, we first examined the correlation between β-catenin/Foxo1 or β-catenin/TCF1 with the severity of kidney fibrosis (Fig. 1a) in kidney biopsies of CKD patients, including those with thin glomerular basement membrane nephropathy, hypertensive nephropathy, diabetic nephropathy, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), mesangiocapillary glomerulonephritis (MCGN), medullary cystic diseases and kidney transplant using a Proximity ligation assay (PLA)
Summary
Kidney fibrosis is characterized by over-production and deposition of extracellular matrix and is considered to be a crucial factor in driving chronic kidney disease (CKD) towards kidney failure [1, 2]. The role of Foxo proteins in the regulation of cell survival has been described by Greer and Brunet [11]. Both TCF and Foxo bind to the armadillo repeats 1–7 on β-catenin [12]. The effect of β-catenin/Foxo interaction versus β-catenin/TCF on TGF-β-induced profibrotic changes was examined in tubular epithelial cells in vitro by CRISPR/cas9-mediated knockout of Foxo or TCF1 and in a kidney fibrosis model, unilateral ureteric obstruction (UUO). We showed that the binding of β-catenin to Foxo protected against TGF-β-induced profibrotic effects and ameliorated kidney fibrosis
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