title: Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis.
abstract: Pericytes have been identified as the major source of precursors of scar-producing myofibroblasts during kidney fibrosis. The underlying mechanisms triggering pericyte-myofibroblast transition are poorly understood. Transforming growth factor β-1 (TGF-β1) is well recognized as a pluripotent cytokine that drives organ fibrosis. We investigated the role of TGF-β1 in inducing profibrotic signaling from epithelial cells to activate pericyte-myofibroblast transition. Increased expression of TGF-β1 was detected predominantly in injured epithelium after unilateral ureteral obstruction, whereas downstream signaling from the TGF-β1 receptor increased in both injured epithelium and pericytes. In mice with ureteral obstruction that were treated with the pan anti-TGF-β antibody (1D11) or TGF-β receptor type I inhibitor (SB431542), kidney pericyte-myofibroblast transition was blunted. The consequence was marked attenuation of fibrosis. In addition, epithelial cell cycle G2/M arrest and production of profibrotic cytokines were both attenuated. Although TGF-β1 alone did not trigger pericyte proliferation in vitro, it robustly induced α smooth muscle actin (α-SMA). In cultured kidney epithelial cells, TGF-β1 stimulated G2/M arrest and production of profibrotic cytokines that had the capacity to stimulate proliferation and transition of pericytes to myofibroblasts. In conclusion, this study identified a novel link between injured epithelium and pericyte-myofibroblast transition through TGF-β1 during kidney fibrosis.
authors.affiliation: Renal Division, Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ching-Fang
authors.initials: CF
authors.lastname: Wu
authors.forename: Wen-Chih
authors.initials: WC
authors.lastname: Chiang
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Lai
authors.forename: Fan-Chi
authors.initials: FC
authors.lastname: Chang
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Chou
authors.forename: Ting-Hui
authors.initials: TH
authors.lastname: Wu
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Linn
authors.forename: Hong
authors.initials: H
authors.lastname: Ling
authors.forename: Kwan-Dun
authors.initials: KD
authors.lastname: Wu
authors.forename: Tun-Jun
authors.initials: TJ
authors.lastname: Tsai
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Chen
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.forename: Shuei-Liong
authors.initials: SL
authors.lastname: Lin
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005355:Fibrosis; D007668:Kidney / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000473:pathology / Q000502:physiology*; D020286:Pericytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D014517:Ureteral Obstruction / Q000150:complications / Q000473:pathology / Q000503:physiopathology
chemical_list: D016207:Cytokines; D053773:Transforming Growth Factor beta1