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

Ito, Shunsuke; Osaka, Mizuko; Edamatsu, Takeo; Itoh, Yoshiharu; Yoshida, Masayuki

doi:10.5551/jat.34462

Cited by 79 publications

(81 citation statements)

References 61 publications

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“…Since IS was identified as a potent endogenous ligand for the aryl hydrocarbon receptor (AhR) (16), an increasing number of studies have focused on the biologic role of the AhR pathway in the pathogenesis of CKD (13,(17)(18)(19). However, the mechanisms underlying the IS-mediated AhR pathway have mainly been explored in renal cells, vascular endothelial cells (VECs), and vascular smooth muscle cells.…”

mentioning

confidence: 99%

Indoxyl sulfate–induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages

Kim

Yoo

Cho³

et al. 2019

FASEB j.

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Indoxyl sulfate (IS) is a uremic toxin associated with increased prevalence of cardiovascular diseases (CVDs) in patients with chronic kidney disease. Despite the crucial role of uremia‐related immune dysfunction, a majority of studies attempting to elucidate its pathogenic role in CVD have focused on IS‐mediated endothelial dysfunction. Thus, we investigated the underlying molecular mechanisms involved in IS‐induced production of TNF‐α, a major cardiotoxic cytokine, by human macrophages. We found that crosstalk between the aryl hydrocarbon receptor (AhR), NF‐κB, and the suppressor of cytokine signaling (SOCS)2 is important for TNF‐α production in IS‐stimulated human macrophages. IS‐activated AhR rapidly associates with the p65 NF‐κB subunit, resulting in mutual inhibition of AhR and NF‐κB and inhibition of TNF‐α production at an early time point. Later, this repression of TNF‐α production is alleviated when SOCS2, a negative modulator of NF‐κB, is directly induced by IS‐activated AhR. In addition, once free of inhibition, activated AhR induces TNF‐α expression by interacting with AhR binding sites in the TNF‐α gene. Lastly, we confirmed decreased AhR and increased SOCS2 expression in monocytes of patients with end‐stage renal disease, indicating the activation of AhR. Taken together, our results suggest that IS‐induced TNF‐α production in macrophages is regulated through a complicated mechanism involving interaction of AhR, NF‐κB, and SOCS2.—Kim, H. Y., Yoo, T.‐H., Cho, J.‐Y., Kim, H. C., Lee, W.‐W. Indoxyl sulfate‐induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages. FASEB J. 33, 10844–10858 (2019). http://www.fasebj.org

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mentioning

confidence: 99%

Indoxyl sulfate–induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages

Kim

Yoo

Cho³

et al. 2019

FASEB j.

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“…At the same time, it has been proven that IS-mediated leukocyte–endothelial interactions affect E/P-selectins expression [60]. Similarly, the progression of vascular damage in essential hypertension is associated with a rise in circulating levels of P-selectins and, to a lesser extent, E-selectins.…”

Section: Discussionmentioning

confidence: 99%

The impact of antihypertensive pharmacotherapy on interplay between protein-bound uremic toxin (indoxyl sulfate) and markers of inflammation in patients with chronic kidney disease

et al. 2019

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PurposeIndoxyl sulfate (IS) is one of the most potent uremic toxins involved in chronic kidney disease (CKD) progression, induction of inflammation, oxidative stress, and cardiovascular diseases occurrence. It is proved that hypertension is a common CVD complication and a major death risk factor as well as contributes for decline in a renal function. The aim of our study was to investigate how implementing of antihypertensive therapy impact IS concentrations and the associations between IS and markers of renal function, inflammation and oxidative stress.MethodsStudy was conducted on 50 patients diagnosed with CKD and hypertension, divided into three groups: without hypotensive therapy (CKD-NONE), hypotensive monotherapy (CKD-MONO), and hypotensive polypharmacotherapy (CKD-POLI), and 18 healthy volunteers. The markers of inflammation [interleukin-6, tumor necrosis factor-alpha (TNF-α), high-sensitive C-reactive protein (hs-CRP), neopterin, ferritin], oxidative status [superoxide dismutase (Cu/Zn-SOD), antibodies against oxidized low-density lipoprotein (oxLDL-abs)], and selectins were determinate using immunoenzymatic methods. IS levels were assayed using high-performance liquid chromatography and other parameters were analysed using routine laboratory techniques. Then cross-sectional analysis was performed.ResultsElevated levels of IS, indicators of kidney function, markers of inflammation and blood pressure values were observed in each CKD subgroups. There was no effect of antihypertensive therapy on IS levels between studied groups, as well as there was no clear relationship between IS and blood pressure values in each studied group. The positive associations between IS and Cu/Zn SOD, neopterin, hs-CRP, creatinine and neutrophils/lymphocytes ratio were observed in CKD-NONE and CKD-POLI subgroups. Additionally, in CKD-POLI group IS positively correlated with TNF-α, ferritin and neutrophils. In CKD-MONO group, IS was positively related to oxLDL-abs, neopterin, E-selectin and creatinine, whereas it was inversely associated with hs-CRP.ConclusionsOur study showed for the first time that the antihypertensive therapy has no impact on IS levels in CKD patients with hypertension. However, the introduction of the antihypertensive therapy modified the dependencies between IS and the studied markers of kidney function, inflammation, oxidative stress and hematological parameters that are crucial for mortality and morbidity amongst the CKD patients with hypertension.Electronic supplementary materialThe online version of this article (10.1007/s11255-018-02064-3) contains supplementary material, which is available to authorized users.

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“…Activating AHR promotes both atherosclerosis in mice with an apolipoprotein E deficiency,37 and leukocyte endothelial interaction induced by TNF‐α 38. The findings of clinical studies have suggested that AHR contributes to thrombotic complications in patients with chronic kidney disease 39, 40.…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

Watanabe

Koyama

Yamashita

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundRecent clinical studies have found that changes in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism are associated with cardiovascular events. However, the roles of the Kyn pathway on vascular wall thrombogenicity remain unknown. Indoleamine 2,3‐dioxygenase 1 (IDO1) is a rate‐limiting enzyme of the Kyn pathway.ObjectiveThe present study aimed to localize IDO1 in human coronary atherosclerotic plaques from patients with angina pectoris and define its role in plaque thrombogenicity.MethodsImmunohistochemical methods were applied to localize IDO1 in coronary atherosclerotic plaques from patients with stable (SAP) and unstable (UAP) angina pectoris. The role of IDO1 in tissue factor (TF) expression was investigated in THP‐1 macrophages activated by interferon (IFN)γ and tissue necrosis factor (TNF)α.ResultsWe localized IDO1 mainly in CD68‐positive macrophages within atherosclerotic plaques, and in close association with TF. Areas that were immunopositive for IDO1, TF, and CD3‐positive T lymphocytes were significantly larger in plaques from patients with UAP than SAP. Macrophages activated by IFNγ and TNFα upregulated IDO1 expression, increased the Kyn/Trp ratio and enhanced TF expression and activity, but not TF pathway inhibitor expression. The IDO1 inhibitor epacadostat significantly reduced the Kyn/Trp ratio, TF expression and activity, as well as NF‐κB (p65) binding activity in activated macrophages. Inhibition of the aryl hydrocarbon receptor that binds to Kyn, also reduced Kyn‐induced TF expression in activated macrophages.ConclusionIndoleamine 2,3‐dioxygenase 1 expressed in coronary atherosclerotic plaques might contribute to thrombus formation through TF upregulation in activated macrophages.

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

Cited by 79 publications

References 61 publications

Indoxyl sulfate–induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages

Indoxyl sulfate–induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages

The impact of antihypertensive pharmacotherapy on interplay between protein-bound uremic toxin (indoxyl sulfate) and markers of inflammation in patients with chronic kidney disease

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

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