Aryl Hydrocarbon Receptor Activation in Chronic Kidney Disease: Role of Uremic Toxins

Brito, Jessyca Sousa de; Borges, Natália Alvarenga; Esgalhado, Marta; Magliano, D’Angelo Carlo; Soulage, Christophe O.; Mafra, Denise

doi:10.1159/000476074

Cited by 68 publications

(56 citation statements)

References 57 publications

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“…In this previous study, we showed that CYP1B1 expression in peripheral monocytes was increased by the treatment with serum of patients with ESRDs who have higher concentrations of serum IS, and this induction was significantly inhibited by the AhR antagonist GNF351 (N-(2-(1H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine) (14). In this context, recent studies suggested that AhR activation by IS in the blood of patients with kidney dysfunction has important pathophysiological implications (17,18). The data in the present study further support the idea that accumulated IS in sera from patients with ESRD causes AhR-dependent induction of SOCS2 and leads to a reduction in the level of AhR by degradation of ligand-activated AhR.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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%

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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“…The product of tryptamine degradation IAA (synonyms: beta-Indolylacetic acid, indolylacetic acid) is also a TrpRS inhibitor [ 46 ] although less potent than tryptamine. IAA is a uremic toxin derived from Trp fermentation by gut microbiota; it accumulates in patients with chronic kidney disease on haemodialysis [ 77 ]. IAA upregulates the eight genes regulated by the transcription factor aryl hydrocarbon receptor (AHR) [ 78 ].…”

Section: Resultsmentioning

confidence: 99%

Towards an Integrative Understanding of tRNA Aminoacylation–Diet–Host–Gut Microbiome Interactions in Neurodegeneration

Paley

Perry

2018

Nutrients

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Transgenic mice used for Alzheimer’s disease (AD) preclinical experiments do not recapitulate the human disease. In our models, the dietary tryptophan metabolite tryptamine produced by human gut microbiome induces tryptophanyl-tRNA synthetase (TrpRS) deficiency with consequent neurodegeneration in cells and mice. Dietary supplements, antibiotics and certain drugs increase tryptamine content in vivo. TrpRS catalyzes tryptophan attachment to tRNAtrp at initial step of protein biosynthesis. Tryptamine that easily crosses the blood–brain barrier induces vasculopathies, neurodegeneration and cell death via TrpRS competitive inhibition. TrpRS inhibitor tryptophanol produced by gut microbiome also induces neurodegeneration. TrpRS inhibition by tryptamine and its metabolites preventing tryptophan incorporation into proteins lead to protein biosynthesis impairment. Tryptophan, a least amino acid in food and proteins that cannot be synthesized by humans competes with frequent amino acids for the transport from blood to brain. Tryptophan is a vulnerable amino acid, which can be easily lost to protein biosynthesis. Some proteins marking neurodegenerative pathology, such as tau lack tryptophan. TrpRS exists in cytoplasmic (WARS) and mitochondrial (WARS2) forms. Pathogenic gene variants of both forms cause TrpRS deficiency with consequent intellectual and motor disabilities in humans. The diminished tryptophan-dependent protein biosynthesis in AD patients is a proof of our model-based disease concept.

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“…82 The AHR is a prominent transcriptional regulator of CYP1A1, 60 and is potently activated by gut-derived protein-bound uremic toxins which accumulate in plasma and tissues in AKI and CKD. 62,63,83,84 This activation is linked with the vascular dysfunction and systemic inflammation of CKD. 62,[85][86][87] In our study, these toxins were increased in urine of SCS pigs, potentially linking to the inflammatory pathways of SCS.…”

Section: Discussionmentioning

confidence: 99%

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

McEvoy

Clotet-Freixas

Tokár

et al. 2020

Preprint

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Normothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid β-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.

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Aryl Hydrocarbon Receptor Activation in Chronic Kidney Disease: Role of Uremic Toxins

Cited by 68 publications

References 57 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

Towards an Integrative Understanding of tRNA Aminoacylation–Diet–Host–Gut Microbiome Interactions in Neurodegeneration

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

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