Indoxyl Sulfate: A Novel Cardiovascular Risk Factor in Chronic Kidney Disease

Hung, Szu Chun; Kuo, Ko‐Lin; Wu, Chih‐Cheng; Tarng, Der Cherng

doi:10.1161/jaha.116.005022

Cited by 154 publications

(127 citation statements)

References 84 publications

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“…Patients with CKD accumulate IS in the body because of a failure to efficiently excrete circulating IS in the urine, which is caused by damaged proximal tubular cells. Multiple lines of evidence show that IS is the most likely uremic toxin participating in the pathophysiology of cardiovascular and renal dysfunction (2,11,13). Because its blood-to-cell transporters and cytosolic sensor were recently identified as organic anion transporters 1, 3, and organic anion transporting polypeptide 2B1 and AhR, respectively (16,47,48), the molecular mechanism underlying the pathogenic role of IS has been intensively explored.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Phenolic and indolic compounds are products of catabolism of aromatic amino acids: phenylalanine, tyrosine and tryptophan are converted by the colonic bacteria to phenylacetate, p ‐cresol and indole, which are further conjugated with glutamine or sulfate in the gut mucosa and the liver to form phenylacetylglutamine, p ‐cresyl sulfate and indoxyl sulfate, respectively, and excreted in the urine. All these molecules are well‐known uraemic toxins which have been associated with CVD , particularly with chronic kidney disease , although their metabolic effects are largely unexplored. Phenylalanine and tyrosine microbial metabolism can also produce other phenolic metabolites such as phenylpropionic acids, phenyllactic acids or hippuric acid .…”

Section: Microbial‐derived Metabolites In Metabolic Health and Diseasementioning

confidence: 99%

Exploration of the microbiota and metabolites within body fluids could pinpoint novel disease mechanisms

Mayneris‐Perxachs

Fernández‐Real

2019

The FEBS Journal

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Thanks to the emergence and recent advances in high‐throughput sequencing technologies, it is becoming more evident every day that changes in the microbiome composition are linked to a myriad of health conditions. Despite this, the mechanisms of host–microbiota signalling remain largely unknown. The microbiome has an extensive metabolic activity that leads to the generation of a large number of compounds that are likely to influence host health. Therefore, the microbiome–host cross‐talk is in part mediated by microbial‐derived metabolites. Unlike metagenomics, which only provides information about microbial genes and thus the microbiome functional potential, metabolic phenotyping is well suited to capture their actual metabolic activity. Here, we provide an overview of these approaches and propose an integration of metagenomics, as a microbiome compositional readout, with faecal and plasma/urine metabolomics, as a functional readout, to unravel novel mechanisms linking the microbiome to host health and disease.

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“…Indole is then absorbed via gut villi and enters the portal system of liver, where it is sulphated and metabolized into IS. Indoxyl sulphate is a protein‐bound small molecule uremic toxin and is harmful for various cells, particularly vascular endothelial cells . In CKD patients, the excretion of IS is impaired, and it is thus accumulated in the body and leads to a vicious cycle .…”

Section: Indoxyl Sulphate a Uremic Toxin Originated From Human Gutmentioning

confidence: 99%

“…[14][15][16] We previously reported that this gut bacteria-derived substance is a potent nephrovascular toxin in CKD patients. [17][18][19][20] Impact of gut microbiome and its derived inflammatory reaction on human health is an emerging research field. Limited but convincing evidence suggests that restoration of symbiosis by dietary prebiotic and/or probiotic supplements may reduce inflammatory parameters and improve clinical outcomes in the CKD population [21][22][23][24][25] ; however, further randomized controlled trials are warranted to examine whether such beneficial effects could be extrapolated to have better hard outcomes.…”

Section: Introductionmentioning

confidence: 99%

Diet, gut microbiome and indoxyl sulphate in chronic kidney disease patients

Yang

Tarng

2018

Nephrology

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Emerging evidence suggests that intestinal dysbiosis plays an important role in host inflammation locally and systemically. Such pathological condition is even more prevailing in patients with chronic kidney disease (CKD). Of note, indoxyl sulphate (IS), a gut‐derived uremic toxin, is notorious for its pro‐inflammatory feature in CKD patients. IS accumulates in the body as the urinary excretion of uremic toxins is impaired, and further worsens the kidney function in a vicious cycle to CKD. Dietary restriction in vegetables, fruits and yogurt leads to the predominance of indole‐producing intestinal microbial flora and further exaggerates the accumulation of IS in CKD patients. Recently, interventional studies have shown that circulating IS can be reduced by dietary prebiotic and/or probiotic supplements. However, further randomized controlled trials are warranted to examine whether such beneficial effect of dietary prebiotic/probiotic supplements could be extrapolated to better hard outcomes in CKD population. In this review, we would also like to emphasize the importance of achieving sufficient intake of dietary fibre by proper vegetable pre‐treatment and accurate fruit selection, instead of directly avoiding these potassium‐rich yet fibre‐rich and base‐producing foods.

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Indoxyl Sulfate: A Novel Cardiovascular Risk Factor in Chronic Kidney Disease

Cited by 154 publications

References 84 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

Exploration of the microbiota and metabolites within body fluids could pinpoint novel disease mechanisms

Diet, gut microbiome and indoxyl sulphate in chronic kidney disease patients

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