Update on the Pharmacokinetics and Redox Properties of Protein-Bound Uremic Toxins

Watanabe, Hiroshi; Miyamoto, Yohei; Otagiri, Masaki; Maruyama, Toru

doi:10.1002/jps.22592

Cited by 100 publications

(80 citation statements)

References 108 publications

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“…Because AhR is a ligand-activated transcriptional factor, we need to further examine how IS stimulates AhR and affects NADPH expression with enhanced ROS production. In addition, in healthy individuals, more than 90% of IS binds to serum albumin 40 and from its molecular structure the bound form of IS does not seem to activate AhR. However, with progression of renal dysfunction, albumin-binding capacity is reduced 41 and the serum level of the unbound form of IS is elevated in patients with CKD (unpublished data), which, in turn, may lead to development of CVD.…”

Section: Discussionmentioning

confidence: 98%

Activation of Aryl Hydrocarbon Receptor Mediates Indoxyl Sulfate-Induced Monocyte Chemoattractant Protein-1 Expression in Human Umbilical Vein Endothelial Cells

Watanabe

Tatebe

Namba

et al. 2013

Circ J

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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.

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Section: Discussionmentioning

confidence: 98%

Activation of Aryl Hydrocarbon Receptor Mediates Indoxyl Sulfate-Induced Monocyte Chemoattractant Protein-1 Expression in Human Umbilical Vein Endothelial Cells

Watanabe

Tatebe

Namba

et al. 2013

Circ J

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“…However, in patients undergoing hemodialysis, IAA levels are not related to protein equivalent of total nitrogen appearance, a reliable estimate of dietary protein intake. 20 IAA is bound to albumin with a high affinity, 21 and the protein binding of IAA is about 80%. 22 IAA is party removed during hemodialysis, with a reduction rate of about 45% during the dialysis session.…”

Section: Discussionmentioning

confidence: 99%

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

Dou

Sallée

Cérini

et al. 2015

Journal of the American Society of Nephrology

254

225

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In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan-Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA.3.73 mM) than in the lower IAA group (IAA,3.73 mM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-kB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-kB pathway.

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“…1 Evidence suggests that accumulation of uremic toxin, especially indoxyl sulfate, is an emerging key mechanism of CVD in CKD. 2,3 Indoxyl sulfate has repeatedly been related to cardiovascular mortality. [4][5][6] Dialysis is usually not powerful to remove protein-bound uremic toxins alone.…”

Section: Introductionmentioning

confidence: 99%

Grape seed proanthocyanidin extract protects human umbilical vein endothelial cells from indoxyl sulfate-induced injury via ameliorating mitochondrial dysfunction

Lu¹,

Lu²,

Zheng

et al. 2015

Renal Failure

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Update on the Pharmacokinetics and Redox Properties of Protein-Bound Uremic Toxins

Cited by 100 publications

References 108 publications

Activation of Aryl Hydrocarbon Receptor Mediates Indoxyl Sulfate-Induced Monocyte Chemoattractant Protein-1 Expression in Human Umbilical Vein Endothelial Cells

Activation of Aryl Hydrocarbon Receptor Mediates Indoxyl Sulfate-Induced Monocyte Chemoattractant Protein-1 Expression in Human Umbilical Vein Endothelial Cells

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

Grape seed proanthocyanidin extract protects human umbilical vein endothelial cells from indoxyl sulfate-induced injury via ameliorating mitochondrial dysfunction

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