Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis

Ching Fang Wu, Wen Chih Chiang, Chun Fu Lai, Fan Chi Chang, Yi Ting Chen, Yu Hsiang Chou, Ting Hui Wu, Geoffrey R. Linn, Hong Ling, Kwan Dun Wu, Tun Jun Tsai, Yung Ming Chen, Jeremy S. Duffield, Shuei Liong Lin

Research output: Contribution to journalArticle

107 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)118-131
Number of pages14
JournalAmerican Journal of Pathology
Volume182
Issue number1
DOIs
Publication statusPublished - Jan 2013
Externally publishedYes

Fingerprint

Pericytes
Myofibroblasts
Transforming Growth Factors
Fibrosis
Kidney
Ureteral Obstruction
Epithelium
Epithelial Cells
Cytokines
Growth Factor Receptors
Cicatrix
Smooth Muscle
Actins
Anti-Idiotypic Antibodies
Cell Cycle

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis. / Wu, Ching Fang; Chiang, Wen Chih; Lai, Chun Fu; Chang, Fan Chi; Chen, Yi Ting; Chou, Yu Hsiang; Wu, Ting Hui; Linn, Geoffrey R.; Ling, Hong; Wu, Kwan Dun; Tsai, Tun Jun; Chen, Yung Ming; Duffield, Jeremy S.; Lin, Shuei Liong.

In: American Journal of Pathology, Vol. 182, No. 1, 01.2013, p. 118-131.

Research output: Contribution to journalArticle

Wu, CF, Chiang, WC, Lai, CF, Chang, FC, Chen, YT, Chou, YH, Wu, TH, Linn, GR, Ling, H, Wu, KD, Tsai, TJ, Chen, YM, Duffield, JS & Lin, SL 2013, 'Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis', American Journal of Pathology, vol. 182, no. 1, pp. 118-131. https://doi.org/10.1016/j.ajpath.2012.09.009
Wu, Ching Fang ; Chiang, Wen Chih ; Lai, Chun Fu ; Chang, Fan Chi ; Chen, Yi Ting ; Chou, Yu Hsiang ; Wu, Ting Hui ; Linn, Geoffrey R. ; Ling, Hong ; Wu, Kwan Dun ; Tsai, Tun Jun ; Chen, Yung Ming ; Duffield, Jeremy S. ; Lin, Shuei Liong. / Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis. In: American Journal of Pathology. 2013 ; Vol. 182, No. 1. pp. 118-131.
@article{95fc6281e8df46058b4a59199552024b,
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.",
author = "Wu, {Ching Fang} and Chiang, {Wen Chih} and Lai, {Chun Fu} and Chang, {Fan Chi} and Chen, {Yi Ting} and Chou, {Yu Hsiang} and Wu, {Ting Hui} and Linn, {Geoffrey R.} and Hong Ling and Wu, {Kwan Dun} and Tsai, {Tun Jun} and Chen, {Yung Ming} and Duffield, {Jeremy S.} and Lin, {Shuei Liong}",
year = "2013",
month = "1",
doi = "10.1016/j.ajpath.2012.09.009",
language = "English",
volume = "182",
pages = "118--131",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis

AU - Wu, Ching Fang

AU - Chiang, Wen Chih

AU - Lai, Chun Fu

AU - Chang, Fan Chi

AU - Chen, Yi Ting

AU - Chou, Yu Hsiang

AU - Wu, Ting Hui

AU - Linn, Geoffrey R.

AU - Ling, Hong

AU - Wu, Kwan Dun

AU - Tsai, Tun Jun

AU - Chen, Yung Ming

AU - Duffield, Jeremy S.

AU - Lin, Shuei Liong

PY - 2013/1

Y1 - 2013/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84871300122&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871300122&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2012.09.009

DO - 10.1016/j.ajpath.2012.09.009

M3 - Article

C2 - 23142380

AN - SCOPUS:84871300122

VL - 182

SP - 118

EP - 131

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 1

ER -