Background: Chronic kidney disease (CKD) is recognized as a common condition that elevates the risk of atherosclerotic cardiovascular disease (CVD). Evidence suggests that increased oxidative stress is an emerging key mechanism of atherosclerosis in CKD. One recent study reported that indoxyl sulfate (IS), a uremic toxin derived from dietary protein, could cause vascular disorder, however, little is known about the mechanism involved. The present study examined the signaling pathway that is activated by IS to induce monocyte chemoattractant protein-1 (MCP-1), which plays an important role in the development of atherosclerosis, in cultured human umbilical vein endothelial cells (HUVEC). Methods and Results:We show that IS enhanced reactive oxygen species (ROS) production, assessed by dihydroethidium staining, by HUVEC. IS also induced the expression of MCP-1, which was measured by enzymelinked immunosorbent assay and real-time reverse transcription-polymerase chain reaction. These changes were suppressed by apocynin, a specific inhibitor of NADPH oxidase. Furthermore, IS induced the expression of NADPH oxidase 4 (Nox4) mRNA. IS-induced stimulation of ERK1/2 and p38 phosphorylation, detected by immunoblotting, was inhibited by apocynin. Finally, IS activated NF-κB, which was suppressed by inhibiting ERK1/2 and p38, resulting in reduced MCP-1 expression. These results suggest that IS increases NADPH oxidase-derived ROS, which in turn, activates the MAPK/NF-κB pathway and leads to induction of MCP-1 expression in HUVEC. Conclusions:These findings raise the possibility that IS plays an important pathophysiological role in the development of CVD in individuals with CKD. (Circ J 2010; 74: 2216 - 2224

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp positive correlation between chronic kidney disease (CKD) and cardiovascular disease (CVD) has been demonstrated, but the causative role of uremic toxin remains unclear. 1-3 A number of retention compounds act as uremic toxins, accumulating in the blood of CKD patient, and elevated circulating uremic toxins negatively affect biological function through induction of oxidative stress. The removal of uremic solutes, therefore, has the potential to prevent CVD. However, protein-bound retention solutes are insufficiently eliminated even by hemodialysis. 4-6 Indoxyl sulfate (IS) is a protein-bound uremic toxin metabolized in the liver from indole, a tryptophan metabolite that is formed by intestinal bacteria. Together with CKD progression, IS accumulates in the blood, which leads to cellular toxicity by inducing oxidative stress. 7In particular, recent studies have suggested that IS is associated with vascular damage by inducing vasoactive substances related to atherogenesis such as chemokines, cytokines or cell adhesion molecules. 8,9 As a possible mechanism of the process, we previously demonstrated that IS mediates monocyte chemoattractant protein-1 (MCP-1) expression in human umbilical vein endothelial cells (HUVECs) by producing reactive oxygen species (ROS) through NADPH oxidase activation. 10 MCP-1 is a chemokine that is involved in early stage of atherosclerosis through the recruitment of monocytes from the blood stream to the subendothelial space. 11-13 Moreover, others have shown that IS-induced vascular damage exhibits inflammatory effects in monocytes, vascular smooth muscle cells or cardiac myocytes.

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.

These results suggested that COPD of Japanese patients may develop partly because of oxidative stress derived from a shortage of antioxidant nutrients, especially of AA and lycopene, as well as GSH while this may not be the case in both ACOS and BA.

No abstract

No abstract

Inhibiting the onset of arteriosclerotic disease, which has been increasing due to the westernized diet and aging, is a significant social challenge. Curcumin, a type of polyphenol, has anti-oxidative effects and anti-inflammatory action and is expected to treat and to have prophylactic effects on different diseases. In this study, we examined the effects of long-term administration of curcumin on vascular aging and chronic inflammation—the causes of arteriosclerotic disease. Eight-week-old C57BL/6J mice were fed with high fat diet (HFD) or 0.1% curcumin-mixed HFD (HFD + Cu) until 80 weeks old (n = 20 for each group). After the breeding, we examined the expression of antioxidant enzymes, heme oxygenase-1 (HO-1), oxidative stress, vascular aging, and inflammatory changes in the aorta. In the HFD group, oxidative stress increased with decreased sirt1 expression in the aorta followed by increased senescent cells and enhanced inflammation. Whereas in the HFD + Cu group, HO-1 was induced in the aorta with the suppression of oxidative stress. Additionally, it was shown that sirt1 expression in the aorta in the HFD + Cu group remained at a level comparable to that of the 8-week-old mice with suppression of increased senescent cells and enhanced inflammation. Consequently, disorders associated with HFD were resolved. These results suggest that curcumin might be a food with a prophylactic function against arteriosclerotic disease.

No abstract