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

Abstract

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.

• Authors: Patrick 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: Kidney international (Kidney Int) Vol. 93 Issue 1 Pg. 173-187 (01 2018) ISSN: 1523-1755 [Electronic] United States
• PMID: 29042082 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Smad3 Protein
• Smad3 protein, mouse
• src-Family Kinases

Topics

• Animals
• Cell Transdifferentiation (drug effects, genetics)
• Cells, Cultured
• Cicatrix (enzymology, genetics, pathology, prevention & control)
• Disease Models, Animal
• Fibrosis
• Gene Expression Profiling
• Gene Expression Regulation
• Gene Regulatory Networks
• Kidney (drug effects, enzymology, pathology)
• Kidney Diseases (enzymology, genetics, pathology, prevention & control)
• Macrophages (drug effects, enzymology, pathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Myofibroblasts (drug effects, enzymology, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Sequence Analysis, RNA
• Signal Transduction
• Single-Cell Analysis
• Smad3 Protein (genetics, metabolism)
• Ureteral Obstruction (drug therapy, enzymology, genetics)
• src-Family Kinases (genetics, metabolism)