Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway.

Autores: García-Jérez A, Luengo A, Carracedo J, Ramírez-Chamond R, Rodriguez-Puyol D, Rodriguez-Puyol M, Calleros L.

J Physiol. 2015 Feb 1;593(3):601-18; discussion 618. doi: 10.1113/jphysiol.2014.283887. Epub 2014 Dec 18.

Link → http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2014.283887/abstract;jsessionid=758D897C821ADAD49D573E93B56EC871.f04t04

Abstract

Patients with chronic kidney disease (CKD) have a higher risk of developing cardiovascular diseases. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which, mostly protein-bound compounds such as indoxyl sulfate (IS) and p-cresyl sulphate, having poor clearance by conventional dialysis, induce endothelial toxicity. However, the molecular mechanism by which uraemic toxins regulate early stages of endothelial dysfunction remains unclear. Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity. In this study, we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia. First, we show that incubation of EA.hy926 cells with human uraemic serum from CKD patients upregulates ILK activity. This ILK activation also occurs when the cells are exposed to IS (25-100 μg ml(-1)), p-cresol (10-100 μg ml(-1)) or both combined, compared to human serum control. Next, we observed that high doses of both toxins together induce a slight decrease in cell proliferation and increase apoptosis and reactive oxygen species production. Interestingly, these toxic effects displayed a strong increase when the ILK protein is knocked down by small interfering RNA, even at low doses of uraemic toxins. Abrogation of AKT has demonstrated the ILK/AKT signalling pathway involved in these processes. This study has demonstrated the implication of ILK in the protection against endothelial cell damage induced by uraemic toxins, a molecular mechanism that could play a protective role in the early stages of endothelial dysfunction observed in uraemic patients.