Dickkopf-3 in aberrant endothelial secretome triggers renal fibroblast activation and endothelial-mesenchymal

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Updated: Feb 11, 2026

In Vitro and In Vivo Models to Study Corneal Endothelial-mesenchymal Transition
09:05

In Vitro and In Vivo Models to Study Corneal Endothelial-mesenchymal Transition

Published on: August 20, 2016

8.4K

Mark Lipphardt1,2, Hassan Dihazi2, Noo Li Jeon3

  • 1Departments of Medicine, Pharmacology and Physiology, Renal Research Institute, New York Medical College at Touro University, Valhalla, NY, USA.

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association
|May 5, 2018
PubMed
Abstract

Insights

Dickkopf-3 (DKK3) promotes kidney fibrosis by activating Wnt signaling, leading to myofibroblast formation and endothelial dysfunction. Sulindac sulfide, a Wnt inhibitor, reduced DKK3 and fibrosis in nephropathy.

Area of Science:

  • Renal pathophysiology
  • Endothelial biology
  • Molecular signaling

Background:

  • Sirt1endo-/- mice exhibit endothelial dysfunction and renal fibrosis.
  • Endothelial transforming growth factor beta (TGF-β) signaling inhibition confers resistance to fibrosis.
  • Contrasting responses suggest secreted factors from endothelium play a key role.

Purpose of the Study:

  • To identify secreted factors from renal microvascular endothelial cells (RMVECs) that contribute to renal fibrosis.
  • To investigate the role of Dickkopf-3 (DKK3) in mediating endothelial dysfunction and fibrosis.

Main Methods:

  • Unbiased proteomic analysis of RMVEC secretomes from mutant mice.
  • In vitro culture of renal fibroblasts and RMVECs.
  • Microfluidic co-culture devices.
  • In vivo studies using reporter mice and adriamycin-induced nephropathy model.

Main Results:

  • DKK3, a Wnt/β-catenin pathway ligand, was exclusively found in the fibrogenic secretome.
  • DKK3 induced myofibroblast activation in fibroblasts and antagonized DKK1 effects.
  • DKK3 promoted endothelial-mesenchymal transition and impaired angiogenesis in RMVECs.
  • DKK3 expression was upregulated in nephropathy; sulindac sulfide suppressed DKK3 and fibrosis.

Conclusions:

  • DKK3 is a profibrogenic endothelial secretome component that activates Wnt signaling.
  • DKK3 promotes myofibroblast formation and endothelial-mesenchymal transition, impairing angiogenesis.
  • Wnt pathway inhibition via sulindac sulfide ameliorates DKK3-induced renal fibrosis.

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