title: Smad3 signaling activates bone marrow-derived fibroblasts in renal fibrosis.
abstract: Recent studies have demonstrated that bone marrow-derived fibroblasts contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow-derived fibroblasts in the kidney are incompletely understood. As TGF-β1/Smad3 signaling has been shown to have an important role in the pathogenesis of kidney fibrosis, we investigated the role of Smad3 in the activation of bone marrow-derived fibroblasts in the kidney following obstructive injury using Smad3-knockout mice and Smad3-null monocytes. Compared with wild-type mice, Smad3-knockout mice accumulated significantly fewer bone marrow-derived fibroblasts in the kidney after obstructive injury. Furthermore, Smad3-knockout mice exhibited less myofibroblast activation and expressed less α-SMA in the obstructed kidney. Consistent with these findings, genetic deletion of Smad3 reduced total collagen deposition and suppressed the expression of extracellular matrix proteins. Moreover, wild-type mice engrafted with Smad3(-/-) bone marrow cells displayed fewer bone marrow-derived fibroblasts in the kidney with obstructive injury and showed less severe renal fibrosis compared with wild-type mice engrafted with Smad3(+/+) bone marrow cells. In cultured monocytes, TGF-β1 induced phosphorylation of Smad3 and Smad3 deficiency abolished TGF-β1-induced expression of α-SMA and extracellular matrix proteins. Taken together, our results demonstrate that Smad3 signaling has an essential role in the activation of bone marrow-derived fibroblasts in the kidney during the pathogenesis of renal fibrosis.
authors.affiliation: Division of Nephrology, Department of Medicine-Nephrology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Department of Medicine-Nephrology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.affiliation: Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: 1] Division of Nephrology, Department of Medicine-Nephrology, Baylor College of Medicine, Houston, TX, USA [2] Medical Care Line, Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, USA.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D009400:Nephrosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse