The proto-oncogene tyrosine protein kinase Src is essential for macrophage-myofibroblast transition during renal scarring

• Published in: Kidney international Vol. 93; no. 1; pp. 173 - 187
• Main Authors: Tang, Patrick Ming-Kuen, Zhou, Shuang, Li, Chun-Jie, Liao, Jinyue, Xiao, Jun, Wang, Qing-Ming, Lian, Guang-Yu, Li, Jinhong, Huang, Xiao-Ru, To, Ka-Fai, NG, Chi-Fai, Chong, Charing Ching-Ning, Ma, Ronald Ching-Wa, Lee, Tin-Lap, Lan, Hui-Yao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2018
• Subjects: Animals; Cell Transdifferentiation - drug effects; Cell Transdifferentiation - genetics; Cells, Cultured; Cicatrix - enzymology; Cicatrix - genetics; Cicatrix - pathology; Cicatrix - prevention & control; Disease Models, Animal; Fibrosis; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Kidney Diseases - enzymology; Kidney Diseases - genetics; Kidney Diseases - pathology; Kidney Diseases - prevention & control; macrophage-myofibroblast transition (MMT); Macrophages - drug effects; Macrophages - enzymology; Macrophages - pathology; Male; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts - drug effects; Myofibroblasts - enzymology; Myofibroblasts - pathology; Protein Kinase Inhibitors - pharmacology; Sequence Analysis, RNA; Signal Transduction; Single-Cell Analysis; single-cell RNA sequencing; Smad3 Protein - genetics; Smad3 Protein - metabolism; Src; src-Family Kinases - genetics; src-Family Kinases - metabolism; Ureteral Obstruction - drug therapy; Ureteral Obstruction - enzymology; Ureteral Obstruction - genetics; single-cell RNA sequencing; macrophage-myofibroblast transition (MMT); Src
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1016/j.kint.2017.07.026

Src 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-β/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-β1-induced elongated fibroblast-like morphology, α-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.