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Rapid Depletion of Renal Macrophages Using Human CD59/Intermedilysin Cell Ablation Tool
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The proto-oncogene tyrosine protein kinase Src is essential for macrophage-myofibroblast transition during renal

Patrick Ming-Kuen Tang1, Shuang Zhou2, Chun-Jie Li3

  • 1Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, and Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.

Kidney International
|October 19, 2017
PubMed

Insights

Src activation drives kidney fibrosis through macrophage-myofibroblast transition. Targeting Src may offer a precision therapy for fibrotic diseases by inhibiting this pathway.

Area of Science:

  • Cell Biology
  • Renal Physiology
  • Molecular Medicine

Background:

  • Src activation is linked to kidney fibrogenesis.
  • Macrophage-to-myofibroblast transition (MMT) generates collagen-producing cells in fibrotic kidneys via TGF-β/Smad3.
  • The role of MMT in Src-mediated renal fibrosis remains unclear.

Purpose of the Study:

  • To investigate the role of MMT in Src-mediated renal fibrosis.
  • To identify the regulatory mechanisms underlying MMT.
  • To explore Src as a therapeutic target for MMT-driven fibrotic diseases.

Main Methods:

  • Single-cell RNA sequencing to identify differentially expressed genes during MMT.
  • In vivo studies using ureteral obstruction model.
  • In vitro studies using bone marrow-derived macrophages stimulated with TGF-β1.
  • Smad3 knockout models.

Main Results:

  • A Src-centric gene network regulating MMT was identified, with 501 differentially expressed genes.
  • Smad3 knockout reduced transcriptome diversity.
  • Src inhibition suppressed MMT in vivo and TGF-β1-induced MMT in vitro, including fibroblast-like morphology, α-smooth muscle actin expression, and collagen production.
  • Src is a direct Smad3 target gene and is upregulated in macrophages during MMT.

Conclusions:

  • MMT contributes to Src-mediated renal fibrosis.
  • Src acts as a key regulator in the MMT process.
  • Targeting Src presents a potential precision therapeutic strategy for fibrotic diseases driven by MMT.
Keywords:
Srcmacrophage-myofibroblast transition (MMT)single-cell RNA sequencing

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