Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide

Area of Science:

• Molecular Biology
• Nephrology
• Cardiovascular Research

Background:

• Endothelial dysfunction is an early event in atherosclerosis development in chronic kidney disease (CKD).
• Epigenetic factors are implicated in CKD-associated endothelial dysfunction.
• Endothelial protective agents like defibrotide (DF) may offer therapeutic benefits.

Purpose of the Study:

• To investigate CKD-induced proteomic changes in endothelial cells.
• To explore the protective effects of defibrotide (DF) on endothelial cells exposed to uraemic serum.
• To elucidate the underlying mechanisms of DF's action, focusing on histone deacetylases (HDACs) and signaling pathways.

Main Methods:

• Human umbilical cord vein endothelial cells were treated with sera from healthy donors and end-stage renal disease patients undergoing hemodialysis.
• Proteomic analysis, Western blot, and immunofluorescence were employed to assess protein expression and localization.
• The effects of DF and trichostatin A (a HDAC inhibitor) were evaluated on endothelial dysfunction markers and HDAC expression.

Main Results:

• CKD sera induced overexpression of HDAC1 and HDAC2 in endothelial cells, with increased HDAC1 in both cytoplasm and nucleus.
• DF and trichostatin A inhibited the upregulation of endothelial dysfunction markers (ICAM-1, TLR-4, vWF, ROS) induced by uraemic milieu.
• DF demonstrated a dose-dependent inhibition of HDACs and downregulated their expression via the PI3K/AKT signaling pathway.

Conclusions:

• HDACs are key regulators of endothelial dysfunction in the context of CKD.
• Specific blockade of HDACs, either by trichostatin A or defibrotide (DF), mitigates endothelial dysfunction responses to CKD insults.
• Defibrotide (DF) exerts its protective effects by inhibiting HDAC upregulation, likely mediated through the PI3K/AKT pathway, suggesting its therapeutic potential.