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Tryptophan-Derived Uremic Toxins and AhR Activation in Chronic Kidney Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 24236

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Dr. Laetitia Dou

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INSERM, INRA, C2VN, Aix Marseille University, 13005 Marseille, France
Interests: uremic toxins; vascular endothelium; chronic kidney disease; cardiovascular disease; thrombosis; aryl hydrocarbon receptor

Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) is a context of the pathological accumulation of tryptophan metabolites. These tryptophan metabolites include uremic toxins from the indolic pathway, like indoxyl sulfate and indole-3 acetic acid, and uremic toxins from the kynurenine pathway, like kynurenine or kynurenic acid. Clinical and basic studies have demonstrated the role of tryptophan-derived uremic toxins in CKD progression, as well as in various complications of CKD like cardiovascular disease, inflammation, thrombosis, anemia, sarcopenia, bone disorders, neuropathy, or abnormal drug metabolism.

Tryptophan-derived uremic toxins share the ability to activate the ligand-dependent transcription factor Aryl hydrocarbon receptor (AhR). Furthermore, hyperglycemia in CKD patients with diabetes—the leading cause of kidney failure—is also an inducer of AhR activation. Thus, the plasma of patients with CKD contains high levels of AhR agonists. Some of the harmful effects of tryptophan-derived uremic toxins are related to their AhR-activating ability, and increasing studies have highlighted the pathogenic role of AhR activation in complications associated with CKD. The study of toxicity mechanisms related to uremic AhR agonists could help to identify new therapeutic targets to prevent the complications in CKD.

I invite authors to submit experimental work or critical reviews that increase the understanding of how tryptophan-derived uremic toxins and/or AhR activation are involved in complications associated with chronic kidney disease. Work focusing more on fundamental molecular study will be appreciated.

Dr. Laetitia Dou
Guest Editor

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Keywords

aryl hydrocarbon receptor
chronic kidney disease
diabetes
uremic toxins
tryptophan metabolism

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Published Papers (6 papers)

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Research

16 pages, 3949 KiB

Open AccessArticle

Modulation of the Paracrine Kynurenic System in Bone as a New Regulator of Osteoblastogenesis and Bone Mineral Status in an Animal Model of Chronic Kidney Disease Treated with LP533401

by Adrian Mor, Krystyna Pawlak, Bartlomiej Kalaska, Tomasz Domaniewski, Beata Sieklucka, Marta Zieminska, Bogdan Cylwik and Dariusz Pawlak

Int. J. Mol. Sci. 2020, 21(17), 5979; https://doi.org/10.3390/ijms21175979 - 19 Aug 2020

Cited by 7 | Viewed by 2634

Abstract

An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy. Full article

(This article belongs to the Special Issue Tryptophan-Derived Uremic Toxins and AhR Activation in Chronic Kidney Disease)

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16 pages, 7016 KiB

Open AccessArticle

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

by Camélia Makhloufi, Fanny Nicolas, Nathalie McKay, Samantha Fernandez, Guillaume Hache, Philippe Garrigue, Philippe Brunet, Benjamin Guillet, Stéphane Burtey and Stéphane Poitevin

Int. J. Mol. Sci. 2020, 21(7), 2483; https://doi.org/10.3390/ijms21072483 - 3 Apr 2020

Cited by 10 | Viewed by 3949

Abstract

Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins—mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR^−/− mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR^−/− males. AhR^−/− females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR^−/− mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD. Full article

(This article belongs to the Special Issue Tryptophan-Derived Uremic Toxins and AhR Activation in Chronic Kidney Disease)

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15 pages, 1678 KiB

Open AccessArticle

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

by Guillaume Lano, Manon Laforêt, Clarissa Von Kotze, Justine Perrin, Tawfik Addi, Philippe Brunet, Stéphane Poitevin, Stéphane Burtey and Laetitia Dou

Int. J. Mol. Sci. 2020, 21(7), 2392; https://doi.org/10.3390/ijms21072392 - 31 Mar 2020

Cited by 18 | Viewed by 3705

Abstract

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. Full article

(This article belongs to the Special Issue Tryptophan-Derived Uremic Toxins and AhR Activation in Chronic Kidney Disease)

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10 pages, 1150 KiB

Open AccessArticle

Difference in Profiles of the Gut-Derived Tryptophan Metabolite Indole Acetic Acid between Transplanted and Non-Transplanted Patients with Chronic Kidney Disease

by Sophie Liabeuf, Solène M. Laville, Griet Glorieux, Lynda Cheddani, François Brazier, Dimitri Titeca Beauport, Raymond Vanholder, Gabriel Choukroun and Ziad A. Massy

Int. J. Mol. Sci. 2020, 21(6), 2031; https://doi.org/10.3390/ijms21062031 - 16 Mar 2020

Cited by 21 | Viewed by 2795

Abstract

Background: Uremic toxins have emerged as potential mediators of morbidity and mortality in patients with chronic kidney disease (CKD). Indole-3-acetic acid (IAA, a tryptophan-derived uremic toxin) might be a useful biomarker in patients with CKD. The objectives of the present study were to (i) describe IAA concentrations in a cohort of non-transplanted patients with CKD and a cohort of transplanted patients with CKD, and (ii) investigate the possible relationship between IAA levels and adverse outcomes in the two cohorts. Methods: Levels of free and total IAA were assayed in the two prospective CKD cohorts (140 non-transplanted patients and 311 transplanted patients). Cox multivariate analyses were used to evaluate the association between IAA levels and outcomes (mortality, cardiovascular events, and graft loss). Results: In the non-transplanted CKD cohort, free and total IAA increased progressively with the CKD stage. In the transplanted CKD cohort, free and total IAA levels were elevated at the time of transplantation but had fallen substantially at one-month post-transplantation. Indole acetic acid concentrations were lower in transplanted patients than non-dialysis non-transplanted patients matched for estimated glomerular filtration rate (eGFR), age, and sex. After adjustment for multiple confounders, the free IAA level predicted overall mortality and cardiovascular events in the non-transplanted CKD cohort (hazard ratio [95% confidence interval]: 2.5 [1.2–5.1] and 2.5 [1.3–4.8], respectively). In the transplanted CKD cohort, however, no associations were found between free or total IAA on one hand, and mortality, CV event, or graft survival on the other. Conclusion: We demonstrated that levels of IAA increase with the CKD stage, and fall substantially, even normalizing, after kidney transplantation. Free IAA appears to be a valuable outcome-associated biomarker in non-transplanted patients, but—at least in our study setting—not in transplanted patients. Full article

(This article belongs to the Special Issue Tryptophan-Derived Uremic Toxins and AhR Activation in Chronic Kidney Disease)

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19 pages, 2275 KiB

Open AccessArticle

Isolation and Quantification of Uremic Toxin Precursor-Generating Gut Bacteria in Chronic Kidney Disease Patients

by Tessa Gryp, Geert R.B. Huys, Marie Joossens, Wim Van Biesen, Griet Glorieux and Mario Vaneechoutte

Int. J. Mol. Sci. 2020, 21(6), 1986; https://doi.org/10.3390/ijms21061986 - 14 Mar 2020

Cited by 76 | Viewed by 6149

Abstract

In chronic kidney disease (CKD), impaired kidney function results in accumulation of uremic toxins, which exert deleterious biological effects and contribute to inflammation and cardiovascular morbidity and mortality. Protein-bound uremic toxins (PBUTs), such as p-cresyl sulfate, indoxyl sulfate and indole-3-acetic acid, originate from phenolic and indolic compounds, which are end products of gut bacterial metabolization of aromatic amino acids (AAA). This study investigates gut microbial composition at different CKD stages by isolating, identifying and quantifying PBUT precursor-generating bacteria. Fecal DNA extracts from 14 controls and 138 CKD patients were used to quantify total bacterial number and 11 bacterial taxa with qPCR. Moreover, isolated bacteria from CKD 1 and CKD 5 fecal samples were cultured in broth medium supplemented with AAA under aerobic and anaerobic conditions, and classified as PBUT precursor-generators based on their generation capacity of phenolic and indolic compounds, measured with U(H)PLC. In total, 148 different fecal bacterial species were isolated, of which 92 were PBUT precursor-generators. These bacterial species can be a potential target for reducing PBUT plasma levels in CKD. qPCR indicated lower abundance of short chain fatty acid-generating bacteria, Bifidobacterium spp. and Streptococcus spp., and higher Enterobacteriaceae and E. coli with impaired kidney function, confirming an altered gut microbial composition in CKD. Full article

(This article belongs to the Special Issue Tryptophan-Derived Uremic Toxins and AhR Activation in Chronic Kidney Disease)

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19 pages, 5044 KiB

Open AccessCommunication

Serum Levels and Removal by Haemodialysis and Haemodiafiltration of Tryptophan-Derived Uremic Toxins in ESKD Patients

by Joosep Paats, Annika Adoberg, Jürgen Arund, Annemieke Dhondt, Anders Fernström, Ivo Fridolin, Griet Glorieux, Liisi Leis, Merike Luman, Emilio Gonzalez-Parra, Vanessa Maria Perez-Gomez, Kristjan Pilt, Didier Sanchez-Ospina, Mårten Segelmark, Fredrik Uhlin and Alberto Arduan Ortiz

Int. J. Mol. Sci. 2020, 21(4), 1522; https://doi.org/10.3390/ijms21041522 - 23 Feb 2020

Cited by 15 | Viewed by 4255

Abstract

Tryptophan is an essential dietary amino acid that originates uremic toxins that contribute to end-stage kidney disease (ESKD) patient outcomes. We evaluated serum levels and removal during haemodialysis and haemodiafiltration of tryptophan and tryptophan-derived uremic toxins, indoxyl sulfate (IS) and indole acetic acid (IAA), in ESKD patients in different dialysis treatment settings. This prospective multicentre study in four European dialysis centres enrolled 78 patients with ESKD. Blood and spent dialysate samples obtained during dialysis were analysed with high-performance liquid chromatography to assess uremic solutes, their reduction ratio (RR) and total removed solute (TRS). Mean free serum tryptophan and IS concentrations increased, and concentration of IAA decreased over pre-dialysis levels (67%, 49%, −0.8%, respectively) during the first hour of dialysis. While mean serum total urea, IS and IAA concentrations decreased during dialysis (−72%, −39%, −43%, respectively), serum tryptophan levels increased, resulting in negative RR (−8%) towards the end of the dialysis session (p < 0.001), despite remarkable Trp losses in dialysate. RR and TRS values based on serum (total, free) and dialysate solute concentrations were lower for conventional low-flux dialysis (p < 0.001). High-efficiency haemodiafiltration resulted in 80% higher Trp losses than conventional low-flux dialysis, despite similar neutral Trp RR values. In conclusion, serum Trp concentrations and RR behave differently from uremic solutes IS, IAA and urea and Trp RR did not reflect dialysis Trp losses. Conventional low-flux dialysis may not adequately clear Trp-related uremic toxins while high efficiency haemodiafiltration increased Trp losses. Full article

(This article belongs to the Special Issue Tryptophan-Derived Uremic Toxins and AhR Activation in Chronic Kidney Disease)

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