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
  • 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. [email protected].
  • 4. Zhangjiang Institute of Fudan University, Shanghai, 201203, China. [email protected].
  • 5. Department of Urology, Zhongshan Hospital, Fudan University; Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China. [email protected].
  • 6. Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. [email protected].
  • # 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.

Products