Fate alteration of bone marrow-derived macrophages ameliorates kidney fibrosis in murine model of unilateral ureteral obstruction.

ABSTRACT

BACKGROUND: Renal fibrosis is a key pathological feature and final common pathway leading to end-stage kidney failure in many chronic kidney diseases. Myofibroblast is the master player in renal fibrosis. However, myofibroblasts are heterogeneous. Recent studies show that bone marrow-derived macrophages transform into myofibroblasts by transforming growth factor (TGF)-ß-induced macrophage-myofibroblast transition (MMT) in renal fibrosis. METHODS: TGF-ß signaling was redirected by inhibition of ß-catenin/T-cell factor (TCF) to increase ß-catenin/Foxo in bone marrow-derived macrophages. A kidney fibrosis model of unilateral ureteral obstruction was performed in EGFP bone marrow chimera mouse. MMT was examined by flow cytometry analysis of GFP+F4/80+α-SMA+ cells from unilateral ureteral obstruction (UUO) kidney, and by immunofluorescent staining of bone marrow-derived macrophages in vitro. Inflammatory and anti-inflammatory cytokines were analysis by enzyme-linked immunosorbent assay. RESULTS: Inhibition of ß-catenin/TCF by ICG-001 combined with TGF-ß1 treatment increased ß-catenin/Foxo1, reduced the MMT and inflammatory cytokine production by bone marrow-derived macrophages, and thereby, reduced kidney fibrosis in the UUO model. CONCLUSIONS: Our results demonstrate that diversion of ß-catenin from TCF to Foxo1-mediated transcription not only inhibits the ß-catenin/TCF-mediated fibrotic effect of TGF-ß, but also enhances its anti-inflammatory action, allowing therapeutic use of TGF-ß to reduce both inflammation and fibrosis at least partially by changing the fate of bone marrow-derived macrophages.