The Uremic Toxin 3-Indoxyl Sulfate Is a Potent Endogenous Agonist for the Human Aryl Hydrocarbon Receptor

Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood of patients with chronic kidney disease (CKD). In addition to the involvement in the progression of CKD, a recent report indicates that IS suppresses hypoxia-inducible factor (HIF)-dependent erythropoietin (EPO) production, suggesting that IS may also contribute to the progression of renal anemia. In this report, we provide evidence that aryl hydrocarbon receptor (AhR) mediates IS-induced suppression of HIF activation and subsequent EPO production. In HepG2 cells, IS at concentrations similar to the blood levels in CKD patients suppressed hypoxia- or cobalt chloride-induced EPO mRNA expression and transcriptional activation of HIF. IS also induced AhR activation, and AhR blockade resulted in abolishment of IS-induced suppression of HIF activation. The HIF transcription factor is a heterodimeric complex composed of HIF-α subunits (HIF-1α and HIF-2α) and AhR nuclear translocator (ARNT). IS suppressed nuclear accumulation of the HIF-α-ARNT complex accompanied by an increase of the AhR-ARNT complex in the nucleus, implying the involvement of interactions among AhR, HIF-α, and ARNT in the suppression mechanism. In rats, oral administration of indole, a metabolic precursor of IS, inhibited bleeding-induced elevation of renal EPO mRNA expression and plasma EPO concentration and strongly induced AhR activation in the liver and renal cortex tissues. Collectively, this study is the first to elucidate the detailed mechanism by which AhR plays an indispensable role in the suppression of HIF activation by IS. Hence, IS-induced activation of AhR may be a potential therapeutic target for treating renal anemia.

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Aryl Hydrocarbon Receptor Activation and Tissue Factor Induction by Fluid Shear Stress and Indoxyl Sulfate in Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21072392 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2392 ◽

Cited By ~ 3

Author(s):

Guillaume Lano ◽

Manon Laforêt ◽

Clarissa Von Kotze ◽

Justine Perrin ◽

Tawfik Addi ◽

...

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Aryl Hydrocarbon Receptor ◽

Tissue Factor ◽

Target Genes ◽

Fluid Shear Stress ◽

Receptor Activation ◽

Indoxyl Sulfate ◽

Uremic Toxin ◽

Aryl Hydrocarbon

Endogenous agonists of the transcription factor aryl hydrocarbon receptor (AHR) such as the indolic uremic toxin, indoxyl sulfate (IS), accumulate in patients with chronic kidney disease. AHR activation by indolic toxins has prothrombotic effects on the endothelium, especially via tissue factor (TF) induction. In contrast, physiological AHR activation by laminar shear stress (SS) is atheroprotective. We studied the activation of AHR and the regulation of TF by IS in cultured human umbilical vein endothelial cells subjected to laminar fluid SS (5 dynes/cm2). SS and IS markedly increased the expression of AHR target genes PTGS2 (encoding for COX2), AHRR, CYP1A1, and CYP1B1, as well as F3 (encoding for TF), in an AHR-dependent way. IS amplified SS-induced TF mRNA and protein expression and upregulation of AHR target genes. Interestingly, tyrosine kinase inhibition by genistein decreased SS- but not IS-induced TF expression. Finally, the increase in TF expression induced by laminar SS was not associated with increased TF activity. In contrast, IS increased TF activity, even under antithrombotic SS conditions. In conclusion, IS and SS induce AHR activation and AHR-dependent TF upregulation by different mechanisms. Impairment of the antithrombotic properties of shear stressed endothelium by toxic AHR agonists could favor cardiovascular diseases in CKD.

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Podocyte Injury Caused by Indoxyl Sulfate, a Uremic Toxin and Aryl-Hydrocarbon Receptor Ligand

PLoS ONE ◽

10.1371/journal.pone.0108448 ◽

2014 ◽

Vol 9 (9) ◽

pp. e108448 ◽

Cited By ~ 36

Author(s):

Osamu Ichii ◽

Saori Otsuka-Kanazawa ◽

Teppei Nakamura ◽

Masaaki Ueno ◽

Yasuhiro Kon ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Indoxyl Sulfate ◽

Uremic Toxin ◽

Podocyte Injury ◽

Receptor Ligand ◽

Aryl Hydrocarbon Receptor Ligand ◽

Aryl Hydrocarbon

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Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms21207483 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7483 ◽

Cited By ~ 1

Author(s):

Wen-Chih Liu ◽

Jia-Fwu Shyu ◽

Yuh-Feng Lin ◽

Hui-Wen Chiu ◽

Paik Seong Lim ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Mapk Pathway ◽

Mapk Signaling ◽

Indoxyl Sulfate ◽

Mitogen Activated Protein Kinase ◽

Uremic Toxin ◽

Aryl Hydrocarbon ◽

The Impact

Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR ligands. Our study explored the impact of IS on osteoblast differentiation and examined the possible mechanism of IS in controlling the expression of osteoblastogenesis markers through an in-depth investigation of AhR signaling. In vivo, we found histological architectural disruption of the femoral bones in 5/6 nephrectomies of young adult IS exposed mice, including reduced Runx2 antigen expression. RSV improved the diaphysis architecture, Runx2 expression, and trabecular quality. In vitro data suggest that IS at 500 and 1000 μM disturbed osteoblastogenesis through suppression of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways, which were found to be downstream of AhR. RSV proved to ameliorate the anti-osteoblastogenic effects of IS through the inhibition of AhR and downstream signaling. Taken together, we demonstrated that the IS/AhR/MAPK signaling pathway plays a crucial role in the inhibition of osteoblastogenesis, and RSV has a potential therapeutic role in reversing the IS-induced decline in osteoblast development and suppressing abnormal bone turnover in chronic kidney disease patients.

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

Journal of Atherosclerosis and Thrombosis ◽

10.5551/jat.34462 ◽

2016 ◽

Vol 23 (8) ◽

pp. 960-975 ◽

Cited By ~ 38

Author(s):

Shunsuke Ito ◽

Mizuko Osaka ◽

Takeo Edamatsu ◽

Yoshiharu Itoh ◽

Masayuki Yoshida

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Crucial Role ◽

Vascular Inflammation ◽

Indoxyl Sulfate ◽

Aryl Hydrocarbon

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Indoxyl glucuronide, a protein-bound uremic toxin, inhibits hypoxia-inducible factor‒dependent erythropoietin expression through activation of aryl hydrocarbon receptor

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2018.09.018 ◽

2018 ◽

Vol 504 (2) ◽

pp. 538-544 ◽

Cited By ~ 10

Author(s):

Hirobumi Asai ◽

Junya Hirata ◽

Mie Watanabe-Akanuma

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Hypoxia Inducible Factor ◽

Uremic Toxin ◽

Aryl Hydrocarbon

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Indoxyl Sulfate, a Uremic Endotheliotoxin

Toxins ◽

10.3390/toxins12040229 ◽

2020 ◽

Vol 12 (4) ◽

pp. 229 ◽

Cited By ~ 8

Author(s):

Guillaume Lano ◽

Stéphane Burtey ◽

Marion Sallée

Keyword(s):

Cardiovascular Health ◽

Plasma Concentrations ◽

Cardiovascular Complications ◽

Indoxyl Sulfate ◽

Uremic Toxin ◽

Prooxidant Effect ◽

Aryl Hydrocarbon ◽

Cardiovascular Morbidity And Mortality ◽

And Control

Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)—derived from tryptophan metabolism—accumulates. IS is involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial dysfunction implicated in cardiovascular morbidity and mortality during CKD. In this review, we describe clinical and experimental evidence for IS endothelial toxicity and focus on the various molecular pathways implicated. In patients with CKD, plasma concentrations of IS correlate with cardiovascular events and mortality, with vascular calcification and atherosclerotic markers. Moreover, IS induces a prothrombotic state and impaired neovascularization. IS reduction by AST-120 reverse these abnormalities. In vitro, IS induces endothelial aryl hydrocarbon receptor (AhR) activation and proinflammatory transcription factors as NF-κB or AP-1. IS has a prooxidant effect with reduction of nitric oxide (NO) bioavailability. Finally, IS alters endothelial cell and endothelial progenitor cell migration, regeneration and control vascular smooth muscle cells proliferation. Reducing IS endothelial toxicity appears to be necessary to improve cardiovascular health in CKD patients.

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Inhibition of indoxyl sulfate-induced intrarenal renin-angiotensin system activation: targeting the aryl hydrocarbon receptor

Translational and Clinical Pharmacology ◽

10.12793/tcp.2017.25.3.114 ◽

2017 ◽

Vol 25 (3) ◽

pp. 114

Author(s):

Muhammad Firman Akbar

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Renin Angiotensin System ◽

Indoxyl Sulfate ◽

Angiotensin System ◽

Renin Angiotensin ◽

Aryl Hydrocarbon ◽

System Activation

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Role of Resveratrol on Indoxyl Sulfate-Induced Endothelial Hyperpermeability via Aryl Hydrocarbon Receptor (AHR)/Src-Dependent Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/5847040 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 9

Author(s):

Eskedar Getachew Assefa ◽

Qiaoqiao Yan ◽

Siameregn Berhe Gezahegn ◽

Maibouge Tanko Mahamane Salissou ◽

Shuiqing He ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Src Kinase ◽

Endothelial Permeability ◽

High Serum ◽

Indoxyl Sulfate ◽

Dietary Polyphenols ◽

Aryl Hydrocarbon ◽

Dependent Pathway ◽

Endothelial Hyperpermeability

Resveratrol (RES), a dietary polyphenol compound, has been shown to possess health benefits due to its anti-inflammatory, antioxidative, and antiatherosclerosis properties. Tryptophan metabolite-derived indoxyl sulfate (IS) is identified as one of the uremic toxins and physiological endogenous ligand/activator of aryl hydrocarbon receptor (AHR), associated with atherosclerosis in chronic kidney disease (CKD) patients. Studies have shown that a high serum level of IS causes deleterious effects on health primarily by inducing oxidative stress and endothelial dysfunction. However, the precise mechanisms are still unclear. Here, we investigated the underlying mechanism of IS effect on endothelial permeability and the role of RES on IS-induced endothelial hyperpermeability via the AHR/Src-dependent pathway. Bovine aorta endothelial cells (BAECs) were cultured and incubated with IS in the presence or absence of RES, and transendothelial electrical resistance (TEER) and permeability of cells were measured. Alongside, AHR, Src kinase, and Vascular Endothelial Cadherin (VE-Cadherin) activation were examined. Our data showed that IS reduced TEER of cells resulting in increased permeability. VE-Cadherin, a vital regulator of endothelial permeability, was also significantly activated in response to IS, which appeared to be associated with changes of endothelial permeability and AHR/Src kinase. Interestingly, in this setting, RES reversed the effect of IS and inhibited the increased activation of Src induced by IS-activated AHR and modulated VE-Cadherin and permeability. CH223191, an inhibitor of AHR, significantly inhibits IS-induced endothelial hyperpermeability. Further analysis with treatment of PP2, an inhibitor of Src abolishing Src activation, suggests downstream factors. All our data indicated that IS upregulated the AHR/Src kinase pathway, and increased endothelial permeability and phosphorylation of VE-Cadherin may be represented and provide new strategies for addressing protective properties of RES against Src kinase involved in AHR-mediated endothelial hyperpermeability. The findings may be crucial for managing diseases in which endothelial permeability is compromised, and the dietary polyphenols are involved.

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