The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in the expression of xenobiotic-metabolizing enzymes, inflammatory cytokines and adhesion molecules. Uremic toxins such as indoxyl sulfate and indole acetic acid are derived from tryptophan fermentation by gut microbiota; they accumulate in patients with chronic kidney disease (CKD) on haemodialysis and have recently emerged as potent ligands of AhR. Therefore, AhR can serve as a mediator in inflammation and cardiovascular diseases in these patients. This review discusses current data that support a link between AhR activation and uremic toxins from gut microbiota in CKD.

Keywords:
Aryl hydrocarbon receptor, Uremic toxins, Inflammation, Chronic kidney disease
1.
Denison MS, Vella LM: The hepatic Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin: species differences in subunit dissociation. Arch Biochem Biophys 1990;277:382-388.
2.
Nguyen LP, Bradfield CA: The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 2008;21:102-116.
3.
Schroeder JC, Dinatale BC, Murray IA, Flaveny CA, Liu Q, Laurenzana EM, Lin JM, Strom SC, Omiecinski CJ, Amin S, Perdew GH: The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 2010;49:393-400.
4.
Heath-Pagliuso S, Rogers WJ, Tullis K, Seidel SD, Cenijn PH, Brouwer A, Denison MS: Activation of the Ah receptor by tryptophan and tryptophan metabolites. Biochemistry 1998;37:11508-11515.
5.
Deltombe O, Van Biesen W, Glorieux G, Massy Z, Dhondt A, Eloot S: Exploring protein binding of uremic toxins in patients with different stages of chronic kidney disease and during hemodialysis. Toxins (Basel) 2015;7:3933-3946.
6.
Dou L, Sallée M, Cerini C, Poitevin S, Gondouin B, Jourde-Chiche N, Fallague K, Brunet P, Calaf R, Dussol B, Mallet B, Dignat-George F, Burtey S: The cardiovascular effect of the uremic solute indole-3 acetic acid. J Am Soc Nephrol 2015;26:876-887.
7.
Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M, Choukroun G, Vanholder R, Massy ZA; European Uremic Toxin Work Group (EUTox): Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 2009;4:1551-1558.
8.
Sallee M, Dou L, Cerini C, Poitevin S, Brunet P, Burtey S: The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease. Toxins (Basel) 2014;6:934-949.
9.
Kamiński TW, Pawlak K, Karbowska M, Myśliwiec M, Pawlak D: Indoxyl sulfate - the uremic toxin linking hemostatic system disturbances with the prevalence of cardiovascular disease in patients with chronic kidney disease. BMC Nephrol 2017;18:35.
10.
Swanson HI, Bradfield CA: The AH-receptor: genetics, structure and function. Pharmacogenetics 1993;3:213-230.
11.
Vondracek J, Machala M: Environmental ligands of the Aryl hydrocarbon receptor and their effects in models of adult liver progenitor cells. Stem Cells Int 2016;2016:4326194.
12.
Hankinson O: The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol 1995;35:307-340.
13.
Gondouin B, Cerini C, Dou L, Sallée M, Duval-Sabatier A, Pletinck A, Calaf R, Lacroix R, Jourde-Chiche N, Poitevin S, Arnaud L, Vanholder R, Brunet P, Dignat-George F, Burtey S: Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. Kidney Int 2013;84:733-744.
14.
Soshilov AA, Denison MS: Ligand promiscuity of Aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Mol Cell Biol 2014;34:1707-1719.
15.
Sun RX, Chong LC, Simmons TT, Houlahan KE, Prokopec SD, Watson JD, Moffat ID, Lensu S, Lindén J, P'ng C, Okey AB, Pohjanvirta R, Boutros PC: Cross-species transcriptomic analysis elucidates constitutive aryl hydrocarbon receptor activity. BMC Genomics 2014;15:1053.
16.
Jaeger C, Tischkau SA: Role of Aryl hydrocarbon receptor in circadian clock disruption and metabolic dysfunction. Environ Health Insights 2016;10:133-141.
17.
Zhang L, Nichols RG, Correll J, Murray IA, Tanaka N, Smith PB, Hubbard TD, Sebastian A, Albert I, Hatzakis E, Gonzalez FJ, Perdew GH, Patterson AD: Persistent organic pollutants modify gut microbiota-host metabolic homeostasis in mice through Aryl hydrocarbon receptor activation. Environ Health Perspect 2015;123:679-688.
18.
Brokken LJ, Lundberg PJ, Spanò M, Manicardi GC, Pedersen HS, Struci?ski P, Góralczyk K, Zviezdai V, Jönsson BA, Bonde JP, Toft G, Lundberg Giwercman Y, Giwercman A: Interactions between polymorphisms in the aryl hydrocarbon receptor signalling pathway and exposure to persistent organochlorine pollutants affect human semen quality. Reprod Toxicol 2014;49:65-73.
19.
Moura-Alves P, Faé K, Houthuys E, Dorhoi A, Kreuchwig A, Furkert J, Barison N, Diehl A, Munder A, Constant P, Skrahina T, Guhlich-Bornhof U, Klemm M, Koehler AB, Bandermann S, Goosmann C, Mollenkopf HJ, Hurwitz R, Brinkmann V, Fillatreau S, Daffe M, Tümmler B, Kolbe M, Oschkinat H, Krause G, Kaufmann SH: AhR sensing of bacterial pigments regulates antibacterial defence. Nature 2014;512:387-392.
20.
Esgalhado M, Borges NA, Mafra D: Could physical exercise help modulate the gut microbiota in chronic kidney disease? Future Microbiol 2016;11:699-707.
21.
Mafra D, Lobo JC, Barros AF, Koppe L, Vaziri ND, Fouque D: Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. Future Microbiol 2014;9:399-410.
22.
Prakash S, Rodes L, Coussa-Charley M, Tomaro-Duchesneau C: Gut microbiota: next frontier in understanding human health and development of biotherapeutics. Biologics 2011;5:71-86.
23.
Edwards JK: Altered gut microbiota in CKD. Nat Rev Nephrol 2016;126.
24.
Barros AF, Borges NA, Ferreira DC, Carmo FL, Rosado AS, Fouque D, Mafra D: Is there interaction between gut microbial profile and cardiovascular risk in chronic kidney disease patients? Future Microbiol 2015;10:517-526.
25.
Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, DeSantis TZ, Ni Z, Nguyen TH, Andersen GL: Chronic kidney disease alters intestinal microbial flora. Kidney Int 2013;83:308-315.
26.
Vaziri ND: CKD impairs barrier function and alters microbial flora of the intestine: a major link to inflammation and uremic toxicity. Curr Opin Nephrol Hypertens 2012;21:587-592.
27.
Mafra D, Barros AF, Fouque D: Dietary protein metabolism by gut microbiota and its consequences for chronic kidney disease patients. Future Microbiol 2013;8:1317-1323.
28.
Lin CJ, Wu V, Wu PC, Wu CJ: Meta-analysis of the associations of p-Cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure. PLoS One 2015;10:e0132589.
29.
Lau WL, Kalantar-Zadeh K, Vaziri ND: The gut as a source of inflammation in chronic kidney disease. Nephron 2015;130:92-98.
30.
Lau WL, Vaziri ND: Urea, a true uremic toxin: the empire strikes back. Clin Sci (Lond) 2017;131:3-12.
31.
Ramezani A, Massy ZA, Meijers B, Evenepoel P, Vanholder R, Raj D: Role of the gut microbiome in uremia: a potential therapeutic target. Am J Kidney Dis 2016;67:483-498.
32.
Vogel CF, Khan EM, Leung PS, Gershwin ME, Chang WL, Wu D, Haarmann-Stemmann T, Hoffmann A, Denison MS: Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-κB. J Biol Chem 2014;289:1866-1875.
33.
Ito S, Osaka M, Edamatsu T, Itoh Y, Yoshida M: Crucial role of the Aryl hydrocarbon receptor (AhR) in indoxyl sulfate-induced vascular inflammation. J Atheroscler Thromb 2016;23:960-975.
34.
Niwa T: Uremic toxicity of indoxyl sulfate. Nagoya J Med Sci 2010;72:1-11.
35.
Zhu W, Stevens AP, Dettmer K, Gottfried E, Hoves S, Kreutz M, Holler E, Canelas AB, Kema I, Oefner PJ: Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 2011;401:3249-3261.
36.
Schepers E, Meert N, Glorieux G, Goeman J, Van der Eycken J, Vanholder R: p-Cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production. Nephrol Dial Transplant 2007;22:592-596.
37.
Meijers BK, De Preter V, Verbeke K, Vanrenterghem Y, Evenepoel P: p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin. Nephrol Dial Transplant 2010;25:219-224.
38.
Lekawanvijit S, Kompa AR, Wang BH, Kelly DJ, Krum H: Cardiorenal syndrome: the emerging role of protein-bound uremic toxins. Circ Res 2012;111:1470-1483.
39.
Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T: Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int 2003;63:1671-1680.
40.
Dou L, Bertrand E, Cerini C, Faure V, Sampol J, Vanholder R, Berland Y, Brunet P: The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int 2004;65:442-451.
41.
Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T: Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transplant 2008;23:1892-1901.
42.
Gross P, Massy ZA, Henaut L, Boudot C, Cagnard J, March C, Kamel S, Drueke TB, Six I: Para-cresyl sulfate acutely impairs vascular reactivity and induces vascular remodeling. J Cell Physiol 2015;230:2927-2935.
43.
Black AP, Cardozo LF, Mafra D: Effects of uremic toxins from the gut microbiota on bone: a brief look at chronic kidney disease. Ther Apher Dial 2015;19:436-440.
44.
Meijers BK, Bammens B, De Moor B, Verbeke K, Vanrenterghem Y, Evenepoel P: Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney Int 2008;73:1174-1180.
45.
Ito S, Yoshida M: Protein-bound uremic toxins: new culprits of cardiovascular events in chronic kidney disease patients. Toxins (Basel) 2014;6:665-678.
46.
Cao XS, Chen J, Zou JZ, Zhong YH, Teng J, Ji J, Chen ZW, Liu ZH, Shen B, Nie YX, Lv WL, Xiang FF, Tan X, Ding XQ: Association of indoxyl sulfate with heart failure among patients on hemodialysis. Clin J Am Soc Nephrol 2015;10:111-119.
47.
Stockler-Pinto MB, Saldanha JF, Yi D, Mafra D, Fouque D, Soulage CO: The uremic toxin indoxyl sulfate exacerbates reactive oxygen species production and inflammation in 3T3-L1 adipose cells. Free Radic Res 2016;50:337-344.
48.
Borges NA, Barros AF, Nakao LS, Dolenga CJ, Fouque D, Mafra D: Protein-bound uremic toxins from gut microbiota and inflammatory markers in chronic kidney disease. J Ren Nutr 2016;26:396-400.
49.
Bolati D, Shimizu H, Yisireyili M, Nishijima F, Niwa T: Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB. BMC Nephrol 2013;14:56.
50.
Ichii O, Otsuka-Kanazawa S, Nakamura T, Ueno M, Kon Y, Chen W, Rosenberg AZ, Kopp JB: Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand. PLoS One 2014;9:e108448.
51.
Enoki Y, Watanabe H, Arake R, Sugimoto R, Imafuku T, Tominaga Y, Ishima Y, Kotani S, Nakajima M, Tanaka M, Matsushita K, Fukagawa M, Otagiri M, Maruyama T: Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1. Sci Rep 2016;6:32084.
52.
Adelibieke Y, Yisireyili M, Ng HY, Saito S, Nishijima F, Niwa T: Indoxyl sulfate induces IL-6 expression in vascular endothelial and smooth muscle cells through OAT3-mediated uptake and activation of AhR/NF-κB pathway. Nephron Exp Nephrol 2014;128:1-8.
53.
Watanabe I, Tatebe J, Namba S, Koizumi M, Yamazaki J, Morita T: Activation of aryl hydrocarbon receptor mediates indoxyl sulfate-induced monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells. Circ J 2013;77:224-230.
54.
Ng HY, Bolati W, Lee CT, Chien YS, Yisireyili M, Saito S, Pei SN, Nishijima F, Niwa T: Indoxyl sulfate downregulates mas receptor via Aryl hydrocarbon receptor/nuclear factor-kappa B, and induces cell proliferation and tissue factor expression in vascular smooth muscle cells. Nephron 2016;133:205-212.
55.
Hwang YJ, Yun MO, Jeong KT, Park JH: Uremic toxin indoxyl 3-sulfate regulates the differentiation of Th2 but not of Th1 cells to lessen allergic asthma. Toxicol Lett 2014;225:130-138.
56.
Ochi A, Mori K, Nakatani S, Emoto M, Morioka T, Motoyama K, Fukumoto S, Imanishi Y, Shoji T, Ishimura E, Inaba M: Indoxyl sulfate suppresses hepatic fetuin-A expression via the aryl hydrocarbon receptor in HepG2 cells. Nephrol Dial Transplant 2015;30:1683-1692.
57.
Shivanna S, Kolandaivelu K, Shashar M, Belghasim M, Al-Rabadi L, Balcells M, Zhang A, Weinberg J, Francis J, Pollastri MP, Edelman ER, Sherr DH, Chitalia VC: The Aryl hydrocarbon receptor is a critical regulator of tissue factor stability and an antithrombotic target in uremia. J Am Soc Nephrol 2016;27:189-201.
58.
Koizumi M, Tatebe J, Watanabe I, Yamazaki J, Ikeda T, Morita T: Aryl hydrocarbon receptor mediates indoxyl sulfate-induced cellular senescence in human umbilical vein endothelial cells. J Atheroscler Thromb 2014;21:904-916.
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2017
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