2. Academic Validation
  3. Midkine promotes renal fibrosis by stabilizing C/EBPβ to facilitate endothelial-mesenchymal transition

Midkine promotes renal fibrosis by stabilizing C/EBPβ to facilitate endothelial-mesenchymal transition

  • Commun Biol. 2024 May 7;7(1):544. doi: 10.1038/s42003-024-06154-0.
Cuidi Xu # 1,  Juntao Chen # 1,  Lifei Liang # 1,  Siyue Chen 1,  Xinhao Niu 1,  Ruirui Sang 2,  Cheng Yang 3 4,  Ruiming Rong 5 6
Affiliations

Affiliations

  • 1 Department of Urology, Zhongshan Hospital, Fudan University; Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.
  • 2 Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 3 Department of Urology, Zhongshan Hospital, Fudan University; Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China. esuperyc@163.com.
  • 4 Zhangjiang Institute of Fudan University, Shanghai, 201203, China. esuperyc@163.com.
  • 5 Department of Urology, Zhongshan Hospital, Fudan University; Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China. rong.ruiming@zs-hospital.sh.cn.
  • 6 Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. rong.ruiming@zs-hospital.sh.cn.
  • # Contributed equally.
PMID: 38714800 DOI: 10.1038/s42003-024-06154-0
Abstract

Numerous myofibroblasts are arisen from endothelial cells (ECs) through endothelial to mesenchymal transition (EndMT) triggered by TGF-β. However, the mechanism of ECs transforms to a different subtype, or whether there exists an intermediate state of ECs remains unclear. In present study, we demonstrate Midkine (MDK) mainly expressed by CD31 + ACTA2+ECs going through partial EndMT contribute greatly to myofibroblasts by spatial and single-cell transcriptomics. MDK is induced in TGF-β treated ECs, which upregulates C/EBPβ and increases EndMT genes, and these effects could be reversed by siMDK. Mechanistically, MDK promotes the binding ability of C/EBPβ with ACTA2 promoter by stabilizing the C/EBPβ protein. In vivo, knockout of Mdk or conditional knockout of Mdk in ECs reduces EndMT markers and significantly reverses fibrogenesis. In conclusion, our study provides a mechanistic link between the induction of EndMT by TGF-β and MDK, which suggests that blocking MDK provides potential therapeutic strategies for renal fibrosis.

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