Promotion of ß-Catenin/Forkhead Box Protein O Signaling Mediates Epithelial Repair in Kidney Injury.

Fibrosis is characterized by progressively excessive deposition of matrix components and may lead to organ failure. Transforming growth factor-ß (TGF-ß) is a key cytokine involved in tissue repair and fibrosis. TGF-ß's profibrotic signaling pathways converge at activation of ß-catenin. ß-Catenin is an important transcription cofactor whose function depends on its binding partner. Promoting ß-catenin binding to forkhead box protein O (Foxo) via inhibition of its binding to T-cell factor (TCF) reduces kidney fibrosis in experimental murine models. Herein, we investigated whether ß-catenin/Foxo diverts TGF-ß signaling from profibrotic to physiological epithelial healing. In an in vitro model of wound healing (scratch assay), and in an in vivo model of kidney injury, unilateral renal ischemia reperfusion, TGF-ß treatment in combination with either ICG-001 or iCRT3 (ß-catenin/TCF inhibitors) increased ß-catenin/Foxo interaction, increased scratch closure by increased cell proliferation and migration, reduced the TGF-ß-induced mesenchymal differentiation, and healed the ischemia reperfusion injury with less fibrosis. In addition, administration of ICG-001 or iCRT3 reduced the contractile activity induced by TGF-ß in C1.1 cells. Together, our results indicate that redirection of ß-catenin binding from TCF to Foxo promotes ß-catenin/Foxo-mediated epithelial repair. Targeting ß-catenin/Foxo may rebuild normal structure of injured kidney.

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

ß-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 ß-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. ß-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 ß-catenin/TCF1 versus ß-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, all P < .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 ß-catenin to TCF1 rather than FoxO1 in renal tubular cells was associated with the fibrogenic response in transplanted kidneys.