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Yes-associated protein regulates podocyte cell cycle re-entry and dedifferentiation in adriamycin-induced nephropathy

Kewei Xie1, Chenqi Xu1, Minfang Zhang1

  • 1Department of Nephrology, Molecular Cell Lab for Kidney Disease, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.

Cell Death & Disease
|December 6, 2019
PubMed

Insights

Adriamycin causes podocytes to re-enter the cell cycle and dedifferentiate by upregulating CDK4 and cyclin D1, a process mediated by yes-associated protein (YAP) signaling. This leads to the overexpression of mesenchymal markers in kidney cells.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Podocytes are terminally differentiated kidney cells with limited proliferation capacity, maintained by cell cycle inhibitors like p21, p27, and p57.
  • Adriamycin-induced nephropathy is characterized by podocyte injury and potential dedifferentiation.

Purpose of the Study:

  • To investigate the role of yes-associated protein (YAP) signaling in adriamycin-induced podocyte cell cycle re-entry and dedifferentiation.
  • To elucidate the molecular mechanisms underlying adriamycin's effects on podocytes.

Main Methods:

  • In vivo studies using mice with adriamycin-induced nephropathy.
  • In vitro experiments involving adriamycin treatment of cultured podocytes.
  • Analysis of cell cycle markers (PCNA, CDK4, Cyclin D1), mesenchymal markers (desmin, snail2), and podocyte-specific markers (WT1, nephrin).
  • Manipulation of YAP signaling using overexpression, RNA interference, and the YAP/TEAD inhibitor verteporfin.

Main Results:

  • Adriamycin induced podocyte proliferation (PCNA+, S-phase increase) and dedifferentiation in vivo and in vitro, with upregulation of CDK4 and Cyclin D1.
  • Overexpression of YAP promoted cell cycle entry, upregulated mesenchymal markers, and downregulated podocyte markers.
  • FGF-basic mimicked adriamycin's effects on cell cycle and marker expression.
  • Inhibition of YAP/TEAD signaling with verteporfin or YAP knockdown reduced adriamycin-induced cell cycle re-entry and Cyclin D1 overexpression.

Conclusions:

  • Adriamycin induces podocyte cell cycle re-entry and dedifferentiation, at least partly through YAP signaling, leading to CDK4 and Cyclin D1 upregulation.
  • YAP signaling plays a crucial role in mediating adriamycin's detrimental effects on podocytes, promoting a mesenchymal phenotype.

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