GSTM1 Modulates Expression of Endothelial Adhesion Molecules in Uremic Milieu

Abstract

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.

Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

“…Uremic serum triggered processes of oxidative stress, cell adhesion as well as inflammation. Decreased antioxidant enzyme activity as well as elevated lipid peroxidation indicated redox imbalances in endothelial cells treated with uremic serum [ 29 ]. Further, in endothelial cells, oxidative stress was induced by uremic serum as reflected by an increase in the formation of reactive oxygen species (ROS) [ 30 , 31 ] via a RAGE-NF-κB dependent pathway [ 30 ].…”

“…Further, in endothelial cells, oxidative stress was induced by uremic serum as reflected by an increase in the formation of reactive oxygen species (ROS) [ 30 , 31 ] via a RAGE-NF-κB dependent pathway [ 30 ]. RAGE-NF-κB signaling as well as glutathione S-transferase μ1 (GSTM-1), which is a downstream gene in the Aryl-Hydrocarbon-Receptor (AhR) signaling pathway, were also responsible for a uremic serum-mediated increase in endothelial expression of adhesion molecules [ 29 , 30 ]. Among inflammatory mediators dysregulated in CKD [ 29 ], increased levels of VCAM-1 and the pro-inflammatory cytokine MCP-1 in uremic endothelial cells led to increased monocyte adhesion and thus increased inflammation [ 30 , 32 ].…”

GSTM1 Copy Number and Kidney Disease in People With HIV

“…There is evidence to suggest that the protective, antioxidant effects of GSTM1 are of greater importance in a uremic environment (i.e., at lower GFR), and this may account for the disparity between risk of incident CKD and kidney failure in this cohort. 8 However, a large study by Zhang et al. 9 also failed to reveal an association between GSTM1 loss and kidney failure in either Black ( n = 796) or White participants ( n = 46,187).…”

“…It is possible that GSTM1 loss is implicated in the pathogenesis of hypertensive renal disease but is less significant in other or HIV-associated pathologies. Alternatively, as oxidative stress is increased in CKD, 8 GSTM1 loss may have had a larger impact on kidney disease progression in the African American Study of Kidney study. It is possible that the potential protective effect of GSTM1 becomes important in declining eGFR and that this association was not captured in our cross-sectional study.…”

GSTM1 Gene, Diet, and Kidney Disease: Implication for Precision Medicine?: Recent Advances in Hypertension

“…In this regard, human umbilical vein endothelial cells exposed to uremic serum exhibited enhanced lipid peroxidation and expression of inflammatory cytokines. 69…”