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

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124 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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Wu, C. F., Chiang, W. C., Lai, C. F., Chang, F. C., Chen, Y. T., Chou, Y. H., Wu, T. H., Linn, G. R., Ling, H., Wu, K. D., Tsai, T. J., Chen, Y. M., Duffield, J. S., & Lin, S. L. (2013). Transforming growth factor β-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis. American Journal of Pathology, 182(1), 118-131. https://doi.org/10.1016/j.ajpath.2012.09.009