Aryl Hydrocarbon Receptor Mediates Indoxyl Sulfate-Induced Cellular Senescence in Human Umbilical Vein Endothelial Cells

Abstract

Aim: Vascular senescence, which is accelerated in individuals with chronic kidney disease (CKD), contributes to the development of cardio-renal syndrome, and various uremic toxins may play important roles in the mechanisms underlying this phenomenon. We recently reported that indoxyl sulfate (IS), a uremic toxin, directly activates aryl hydrocarbon receptor (AhR) and generates oxidative stress through NADPH oxidase-4 in human umbilical vein endothelial cells (HUVECs). In the current study, we sought to examine whether IS regulates sirtuin 1 (Sirt1) and affects endothelial senescence via AhR activation.

Molecular Hydrogen Alleviates Cellular Senescence in Endothelial Cells

“…18, 19 In the present study, we evaluated the NAD + /NADH ratio and Sirt1 activity accordance with a previous report. 24 As shown in Figure 8, chrysin treatment abolished the antioxidative and anti-senescence effects of hydrogen on HUVECs at 24 h after TCDD exposure.…”

“…A chrysin concentration of 10 μmol/L was selected, in IS reduced cellular NAD + and suppressed Sirt1 activity, thereby accelerating cellular senescence. 18, 19 When we first examined whether H2 suppresses oxidative stress by means of the TCDD-AhR pathway, we found that in hydrogen-rich medium, the TCDD-induced increase in 8OHdG in HUVECs was significantly suppressed and that these effects were similar to those of the AhR-inhibitor, CH. We then sought to determine whether the antioxidative effects of H2 in HUVECs depended on inhibition of AhR.…”

“…34 We previously reported that a decrease in cellular NAD + caused by ROS production suppressed Sirt1 activity, which resulted in accelerated cellular senescence. 17- 19 Other studies reported that oxidative stress and cellular senescence were ameliorated in endothelial cells that overexpressed Sirt1. 35 In the present study, we examined if NAD + -Sirt1 activation had a role in the H2-induced decrease in acetyl-p53 expression in HUVECs incubated with TCDD.…”

“…Increased ROS decreases intracellular nicotinamide adenine dinucleotide (NAD + ), thereby impairing activation of sirtuin 1 (Sirt1) and ultimately facilitating cellular senescence. [17][18][19] In light of previous findings, we examined the effects of H2 on human umbilical vein endothelial cell (HUVEC) senescence and the AhR-ROS pathway in relation to timedependent change in H2 concentration in medium and found that H2 exerts sustained effects despite its transient presence in medium.…”

Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

“…Moreover, Barreto et al showed that serum indoxyl sulfate progressively increases with stages of chronic kidney disease and is associated with the incidence of cardiovascular disease and overall mortality in patients with chronic kidney disease 12) . Several studies have suggested that indoxyl sulfate aggravates cardiovascular disease by inducing cardiac cell fibrosis, endothelial senescence, proliferation of vascular smooth muscle cells, and activation of monocytes/ macrophages via an oxidative stress-dependent pathway [14][15][16][17][18][19][20][21][22] . In addition, we previously showed that indoxyl sulfate enhances cytokine-induced leukocyteendothelial interactions through E-selectin in vivo and in vitro, and this process is mediated by activation of oxidative stress-dependent intracellular signaling such as JNK and NF-B in human umbilical vein endothelial cells (HUVEC) 23) .…”