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

Abstract

Altres ajuts: This work was supported by Jazz Pharmaceuticals Plc (IST-16-10355 to MDR. and EC); German José Carreras Leukaemia Foundation (Grant 11R/2016 and 03R/2019 to MDR. and EC); [...]. We would like to thank the Proteomics unit staff (CCIT, University of Barcelona) for their support in the proteomic assay performance and analysis, and to the Primary Hemostasis laboratory group for their technical support. We also acknowledge the collaboration of Dr Josep Maria Cruzado of Institut d'Hemodiàlisi Barcelona who collaborated in obtaining the blood samples, the staff of the Maternitat Hospital, in Barcelona, for providing the umbilical cords that made possible some of the current results and to Shook Studio for the visual abstract design.

Endothelial dysfunction is an earlier contributor to the development of atherosclerosis in chronic kidney disease (CKD), in which the role of epigenetic triggers cannot be ruled out. Endothelial protective strategies, such as defibrotide (DF), may be useful in this scenario. We evaluated changes induced by CKD on endothelial cell proteome and explored the effect of DF and the mechanisms involved. Human umbilical cord vein endothelial cells were exposed to sera from healthy donors (n = 20) and patients with end-stage renal disease on haemodialysis (n = 20). Differential protein expression was investigated by using a proteomic approach, Western blot and immunofluorescence. HDAC1 and HDAC2 overexpression was detected. Increased HDAC1 expression occurred at both cytoplasm and nucleus. These effects were dose-dependently inhibited by DF. Both the HDACs inhibitor trichostatin A and DF prevented the up-regulation of the endothelial dysfunction markers induced by the uraemic milieu: intercellular adhesion molecule-1, surface Toll-like receptor-4, von Willebrand Factor and reactive oxygen species. Moreover, DF down-regulated HDACs expression through the PI3/AKT signalling pathway. HDACs appear as key modulators of the CKD-induced endothelial dysfunction as specific blockade by trichostatin A or by DF prevents endothelial dysfunction responses to the CKD insult. Moreover, DF exerts its endothelial protective effect by inhibiting HDAC up-regulation likely through PI3K/AKT.