The proto-oncogene tyrosine protein kinase Src is essential for macrophage-myofibroblast transition during renal scarring
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AbstractSrc activation has been associated with fibrogenesis after kidney injury. Macrophage-myofibroblast transition is a newly identified process to generate collagen-producing myofibroblasts locally in the kidney undergoing fibrosis in a TGF-beta/Smad3-dependent manner. The potential role of the macrophage-myofibroblast transition in Src-mediated renal fibrosis is unknown. In studying this by RNA sequencing at single-cell resolution, we uncovered a unique Src-centric regulatory gene network as a key underlying mechanism of macrophage-myofibroblast transition. A total of 501 differentially expressed genes associated with macrophage-myofibroblast transition were identified. However, Smad3-knockout largely reduced the transcriptome diversity. More importantly, inhibition of Src largely suppresses ureteral obstruction-induced macrophage-myofibroblast transition in the injured kidney in vivo along with transforming growth factor-beta 1-induced elongated fibroblast-like morphology, alpha-smooth muscle actin expression and collagen production in bone marrow derived macrophages in vitro. Unexpectedly, we further uncovered that Src serves as a direct Smad3 target gene and also specifically up-regulated in macrophages during macrophage-myofibroblast transition. Thus, macrophage-myofibroblast transition contributes to Src-mediated tissue fibrosis. Hence, targeting Src may represent as a precision therapeutic strategy for macrophage-myofibroblast transition-driven fibrotic diseases.
Acceptance Date27/07/2017
All Author(s) ListPatrick Ming-Kuen Tang, Shuang Zhou, Chun-Jie Li, Jinyue Liao, Jun Xiao, Qing-Ming Wang, Guang-Yu Lian, Jinhong Li, Xiao-Ru Huang, Ka-Fai To, Chi-Fai NG, Charing Ching-Ning Chong, Ronald Ching-Wa Ma, Tin-Lap Lee, Hui-Yao Lan
Journal nameKidney International
Year2018
Month1
Volume Number93
Issue Number1
PublisherElsevier
Pages173 - 187
ISSN0085-2538
eISSN1523-1755
LanguagesEnglish-United Kingdom
Keywordsmacrophage-myofibroblast transition (MMT),single-cell RNA sequencing,Src
Web of Science Subject CategoriesUrology & Nephrology;Urology & Nephrology

Last updated on 2020-27-09 at 02:40