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

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)-beta-induced macrophage-myofibroblast transition (MMT) in renal fibrosis. Methods. TGF-beta signaling was redirected by inhibition of beta-catenin/T-cell factor (TCF) to increase beta-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(+)alpha-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 beta-catenin/TCF by ICG-001 combined with TGF-beta 1 treatment increased beta-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 beta-catenin from TCF to Foxo1-mediated transcription not only inhibits the beta-catenin/TCF-mediated fibrotic effect of TGF-beta, but also enhances its anti-inflammatory action, allowing therapeutic use of TGF-beta to reduce both inflammation and fibrosis at least partially by changing the fate of bone marrow-derived macrophages.