Deletion polymorphism of
glutathione S-transferase M1 (GSTM1), a phase II detoxification and
antioxidant enzyme, increases susceptibility to
end-stage renal disease (
ESRD) as well as the development of
cardiovascular diseases (CVD) among
ESRD patients and leads to their shorter cardiovascular survival. The mechanisms by which GSTM1 downregulation contributes to oxidative stress and
inflammation in endothelial cells in uremic conditions have not been investigated so far. Therefore, the aim of the present study was to elucidate the effects of GSTM1 knockdown on oxidative stress and expression of a panel of inflammatory markers in human umbilical vein endothelial cells (HUVECs) exposed to uremic serum. Additionally, we aimed to discern whether GSTM1-null genotype is associated with serum levels of adhesion molecules in
ESRD patients. HUVECs treated with uremic serum exhibited impaired redox balance characterized by enhanced lipid peroxidation and decreased
antioxidant enzyme activities, independently of the GSTM1 knockdown. In response to uremic injury, HUVECs exhibited alteration in the expression of a series of inflammatory
cytokines including
retinol-binding protein 4 (RBP4), regulated on activation, normal T cell expressed and secreted (
RANTES),
C-reactive protein (CRP),
angiogenin, dickkopf-1 (Dkk-1), and
platelet factor 4 (PF4). GSTM1 knockdown in HUVECs showed upregulation of
monocyte chemoattractant protein-1 (MCP-1), a
cytokine involved in the regulation of monocyte migration and adhesion. These cells also have shown upregulated intracellular and vascular
cell adhesion molecules (ICAM-1 and VCAM-1). In accordance with these findings, the levels of serum
ICAM-1 and
VCAM-1 (sICAM-1 and sVCAM-1) were increased in
ESRD patients lacking GSTM1, in comparison with patients with the GSTM1-active genotype. Based on these results, it may be concluded that incubation of endothelial cells in uremic serum induces redox imbalance accompanied with altered expression of a series of
cytokines involved in
arteriosclerosis and
atherosclerosis. The association of GSTM1 downregulation with the altered expression of adhesion molecules might be at least partly responsible for the increased susceptibility of
ESRD patients to CVD.