Renal tubular cell binding of β-catenin to TCF1 versus FoxO1 is associated with chronic interstitial fibrosis in transplanted kidneys

beta-Catenin is an important co-factor which binds multiple transcriptional molecules and mediates fibrogenic signaling pathways. Its role in kidney transplantation is unknown. We quantified binding of beta-catenin within renal tubular epithelial cells to transcription factors, TCF1 and FoxO1, using a proximity ligation assay in 240 transplanted kidneys, and evaluated their pathological and clinical outcomes. beta-Catenin/FoxO1 binding in 1-month protocol biopsies inversely correlated with contemporaneous chronic fibrosis, subsequent inflammation. and inflammatory fibrosis (P < .001). The relative binding of beta-catenin/TCF1 versus beta-catenin/FoxO1 (TF ratio) was the optimal biomarker, and abnormal in diverse fibrotic transplant diseases. A high 1-month TF ratio was followed by greater tubular atrophy and interstitial fibrosis scores, cortical inflammation, renal impairment, and proteinuria at 1 year (n = 131, allP < .001). The TF ratio was associated with reduced eGFR (AUC 0.817), mild fibrosis (AUC 0.717), and moderate fibrosis (AUC 0.769) using receiver operating characteristic analysis. An independent validation cohort (n = 76) confirmed 1-month TF was associated with 12-month moderate fibrosis (15.8% vs. 2.6%,P = .047), however, not with other outcomes or 10-year graft survival, which limits generalizabilty of these findings. In summary, differential binding of beta-catenin to TCF1 rather than FoxO1 in renal tubular cells was associated with the fibrogenic response in transplanted kidneys.

Automated summary

Beta-catenin plays a role in fibrogenic signaling pathways, and its differential binding to TCF1 rather than FoxO1 in renal tubular cells is associated with the fibrogenic response in transplanted kidneys. The TF ratio, reflecting the relative binding of beta-catenin/TCF1 versus beta-catenin/FoxO1, is an optimal biomarker for predicting pathological and clinical outcomes in transplant kidneys.