Aryl hydrocarbon receptor (AhR) and its endogenous agonist – indoxyl sulfate in chronic kidney disease
Tomasz Kamiński 1 , Małgorzata Michałowska 1 , Dariusz Pawlak 1Abstract
The indoxyl sulfate (IS, indoxyl sulphate) is the end product of dietary tryptophan degradation by indole pathway and significantly higher serum and tissue concentrations of this compound is observed in patients with impaired renal function. Despite the high albumin binding affinity, the remaining free fraction of IS has a number of biological effects related to the generation of oxidative stress andactivation of signaling pathways related to NF-кB, p53 protein, STAT3, TGF-β and Smad2/3. IS induces the inflammatory process, exerts nephrotoxic activity and is also a factor impairing the cardiovascular system.Its high concentrations are associated with the occurrence of cardiovascular incidents, whose frequency is significantly higher in patients with chronic kidney disease. Evaluation of the mechanisms that underlie the high reactivity of indoxyl sulfate and its biological effects showed that this compound is an agonist of the aryl hydrocarbon receptor (AhR). This receptor plays an important role in maintaining homeostasis Moreover, AhR exerts high transcriptional activity, so ligands of obciążethis receptor may exert different biological effects. The following paper describes the role of indoxyl sulfate as AhR ligand in the context of the excessive accumulation, which appears as one of the symptoms associated with chronic kidney disease.
References
- 1. Abel J., Haarmann-Stemmann T.: An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol. Chem., 2010; 391: 1235-1248
Google Scholar - 2. Adelibieke Y., Shimizu H., Muteliefu G., Bolati D., Niwa T.: Indoxyl sulfate induces endothelial cell senescence by increasing reactive oxygen species production and p53 activity. J. Ren. Nutr., 2012; 22: 86-89
Google Scholar - 3. Adijiang A., Shimizu H., Higuchi Y., Nishijima F., Niwa T.: Indoxyl sulfate reduces klotho expression and promotes senescence in the kidneys of hypertensive rats. J. Ren. Nutr., 2011; 21: 105-109
Google Scholar - 4. Andersson H., Garscha U., Brittebo E.: Effects of PCB126 and 17β-oestradiol on endothelium-derived vasoactive factors in human endothelial cells. Toxicology, 2011; 285: 46-56
Google Scholar - 5. Asai H., Hirata J., Hirano A., Hirai K., Seki S., Watanabe-Akanuma M.: Activation of aryl hydrocarbon receptor mediates suppression of hypoxia-inducible factor-dependent erythropoietin expression by indoxyl sulfate. Am. J. Physiol. Cell Physiol., 2016; 310: C142-C150
Google Scholar - 6. Baba T., Mimura J., Nakamura N., Harada N., Yamamoto M., Morohashi K., Fujii-Kuriyama Y.: Intrinsic function of the aryl hydrocarbon (dioxin) receptor as a key factor in female reproduction. Mol. Cell. Biol., 2005; 25: 10040-10051
Google Scholar - 7. Bock K.W.: Regulation of bilirubin clearance by ligand-activated transcription factors of the endo- and xenobiotic metabolism system. Front. Pharmacol., 2011; 2: 82
Google Scholar - 8. Bock K.W.: The human Ah receptor: hints from dioxin toxicities to deregulated target genes and physiological functions. Biol. Chem., 2013; 394: 729-739
Google Scholar - 9. Bock K.W., Köhle C.: The mammalian aryl hydrocarbon (Ah) receptor: from mediator of dioxin toxicity toward physiological functions in skin and liver. Biol. Chem., 2009; 390: 1225-1235
Google Scholar - 10. 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
Google Scholar - 11. Brinkman A.M., Wu J., Ersland K., Xu W.: Estrogen receptor α and aryl hydrocarbon receptor independent growth inhibitory effects of aminoflavone in breast cancer cells. BMC Cancer, 2014; 14: 344
Google Scholar - 12. Carreira V.S., Fan Y., Wang Q., Zhang X., Kurita H., Ko C.I., Naticchioni M., Jiang M., Koch S., Medvedovic M., Xia Y., Rubinstein J., Puga A.: Ah receptor signaling controls the expression of cardiac development and homeostasis genes. Toxicol. Sci., 2015; 147: 425-435
Google Scholar - 13. Casado F.L., Singh K.P., Gasiewicz T.A.: Aryl hydrocarbon receptor activation in hematopoietic stem/progenitor cells alters cell function and pathway-specific gene modulation reflecting changes in cellular trafficking and migration. Mol. Pharmacol., 2011; 80: 673-682
Google Scholar - 14. Denison M.S., Nagy S.R.: Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol., 2003; 43: 309-334
Google Scholar - 15. Denison M.S., Soshilov A.A., He G., DeGroot D.E., Zhao B.: Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci., 2011; 124: 1-22
Google Scholar - 16. Deshmane S.L., Kremlev S., Amini S., Sawaya B.E.: Monocyte chemoattractant protein-1 (MCP-1): an overview. J. Interferon Cytokine Res., 2009; 29: 313-326
Google Scholar - 17. Devine E., Krieter D.H., Rüth M., Jankovski J., Lemke H.D.: Binding affinity and capacity for the uremic toxin indoxyl sulfate. Toxins, 2014; 6: 416-429
Google Scholar - 18. Di Angelantonio E., Chowdhury R., Sarwar N., Aspelund T., Danesh J., Gudnason V.: Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population based cohort study. Br. Med. J., 2010; 341: c4986
Google Scholar - 19. Duranton F., Cohen G., De Smet R., Rodriguez M., Jankowski J., Vanholder R., Argiles A., European Uremic Toxin Work Group: Normal and pathologic concentrations of uremic toxins. J. Am. Soc. Nephrol., 2012; 23: 1258-1270
Google Scholar - 20. Ellis R.J., Small D.M., Vesey D.A., Johnson D.W., Francis R., Vitetta L., Morais C.: Indoxyl sulphate and kidney disease: causes, consequences and interventions. Nephrology, 2016; 21: 170-177
Google Scholar - 21. Fisher J.M., Jones K.W., Whitlock J.P.Jr.: Activation of transcription as a general mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin action. Mol. Carcinog., 1989; 14: 216-221
Google Scholar - 22. Fressatto de Godoy M.A., Pernomian L., de Oliveira A.M., Rattan S.: Biosynthetic pathways and the role of the MAS receptor in the effects of angiotensin-(1-7) in smooth muscles. Int. J. Hypertens., 2012; 2012: 121740
Google Scholar - 23. Gao C., Ji S., Dong W., Qi Y., Song W., Cui D., Shi J.: Indolic uremic solutes enhance procoagulant activity of red blood cells through phosphatidylserine exposure and microparticle release. Toxins, 2015; 7: 4390-4403
Google Scholar - 24. Gelasco A.K., Raymond J.R.: Indoxyl sulfate induces complex redox alterations in mesangial cells. Am. J. Physiol. Renal Physiol., 2006; 290: F1551-F1558
Google Scholar - 25. 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
Google Scholar - 26. Hirata J., Hirai K., Asai H., Matsumoto C., Inada M., Miyaura C., Yamato H., Watanabe-Akanuma M.: Indoxyl sulfate exacerbates low bone turnover induced by parathyroidectomy in young adult rats. Bone, 2015; 79: 252-258
Google Scholar - 27. Hu C.J., Wang L.Y., Chodosh L.A., Keith B., Simon M.C.: Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol. Cell. Biol., 2003; 23: 9361-9374
Google Scholar - 28. Huang G., Elferink C.J.: A novel nonconsensus xenobiotic response element capable of mediating aryl hydrocarbon receptor- -dependent gene expression. Mol. Pharmacol., 2012; 81: 338-347
Google Scholar - 29. Hyun H.S., Paik K.H., Cho H.Y.: p-Cresyl sulfate and indoxyl sulfate in pediatric patients on chronic dialysis. Korean J. Pediatr., 2013; 56: 159-164
Google Scholar - 30. Ichii O., Otsuka-Kanazawa S., Nakamura T., Ueno M., Kon Y., Chen W., Rosenberg A.Z., Kopp J.B.: Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand. PLoS One, 2014; 9: e108448
Google Scholar - 31. Ito S., Higuchi Y., Yagi Y., Nishijima F., Yamato H., Ishii H., Osaka M., Yoshida M.: Reduction of indoxyl sulfate by AST-120 attenuates monocyte inflammation related to chronic kidney disease. J. Leukoc. Biol., 2013; 93: 837-845
Google Scholar - 32. Ito S., Osaka M., Higuchi Y., Nishijima F., Ishii H., Yoshida M.: Indoxyl sulfate induces leukocyte-endothelial interactions through up-regulation of E-selectin. J. Biol. Chem., 2010; 285: 38869-38875
Google Scholar - 33. Juan S.H., Lee J.L., Ho P.Y., Lee Y.H., Lee W.S.: Antiproliferative and antiangiogenic effects of 3-methylcholanthrene, an aryl-hydrocarbon receptor agonist, in human umbilical vascular endothelial cells. Eur. J. Pharmacol., 2006; 530: 1-8
Google Scholar - 34. Kadow S., Jux B., Zahner S.P., Wingerath B., Chmill S., Clausen B.E., Hengstler J., Esser C.: Aryl hydrocarbon receptor is critical for homeostasis of invariant gδ T cells in the murine epidermis. J. Immunol., 2011; 187: 3104-3110
Google Scholar - 35. Kharait S., Haddad D.J., Springer M.L.: Nitric oxide counters the inhibitory effects of uremic toxin indoxyl sulfate on endothelial cells by governing ERK MAP kinase and myosin light chain activation. Biochem. Biophys. Res. Commun., 2011; 409: 758-763
Google Scholar - 36. Kim Y.H., Kwak K.A., Gil H.W., Song H.Y., Hong S.Y.: Indoxyl sulfate promotes apoptosis in cultured osteoblast cells. BMC Pharmacol. Toxicol., 2013; 14: 60
Google Scholar - 37. Kimura J., Ichii O., Otsuka S., Sasaki H., Hashimoto Y., Kon Y.: Close relations between podocyte injuries and membranous proliferative glomerulonephritis in autoimmune murine models. Am. J. Nephrol., 2013; 38: 27-38
Google Scholar - 38. Kobayashi N., Maeda A., Horikoshi S., Shirato I., Tomino Y., Ise M.: Effects of oral adsorbent AST-120 (Kremezin) on renal function and glomerular injury in early-stage renal failure of subtotal nephrectomised rats. Nephron, 2002; 91: 480-485
Google Scholar - 39. 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
Google Scholar - 40. Kopf P.G., Huwe J.K., Walker M.K.: Hypertension, cardiac hypertrophy, and impaired vascular relaxation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin are associated with increased superoxide. Cardiovasc. Toxicol., 2008; 8: 181-193
Google Scholar - 41. Kopf P.G., Scott J.A., Agbor L.N., Boberg J.R., Elased K.M., Huwe J.K., Walker M.K.: Cytochrome P4501A1 is required for vascular dysfunction and hypertension induced by 2,3,7,8-tetrachlorodibenzo- -p-dioxin. Toxicol. Sci., 2010; 117: 537-546
Google Scholar - 42. Kunkel E.J., Ley K.: Distinct phenotype of E-selectin-deficient mice. E-selectin is required for slow leukocyte rolling in vivo. Circ. Res., 1996; 79: 1196-1204
Google Scholar - 43. Lee J.H., Lee J.: Indole as an intercellular signal in microbial communities. FEMS Microbiol. Rev., 2010; 34: 426-444
Google Scholar - 44. Lindsey S., Jiang J., Woulfe D., Papoutsakis E.T.: Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen-dependent signaling. J. Thromb. Haemost., 2014; 12: 383-394
Google Scholar - 45. Miyamoto Y., Watanabe H., Otagiri M., Maruyama T.: New insight into the redox properties of uremic solute indoxyl sulfate as a proand anti-oxidant. Ther. Apher. Dial., 2011; 15: 129-131
Google Scholar - 46. Miyazaki T., Aoyama I., Ise M., Seo H., Niwa T.: An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF‐β1 in uraemic rat kidneys. Nephrol. Dial. Transplant., 2000; 15: 1773-1781
Google Scholar - 47. Mohammadi-Bardbori A., Bengtsson J., Rannug U., Rannug A., Wincent E.: Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Chem. Res. Toxicol., 2012; 25: 1878-1884
Google Scholar - 48. Murray I.A., Patterson A.D., Perdew G.H.: Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat. Rev. Cancer, 2014; 14: 801-814
Google Scholar - 49. Muteliefu G., Enomoto A., Niwa T.: Indoxyl sulfate promotes proliferation of human aortic smooth muscle cells by inducing oxidative stress. J. Ren. Nutr., 2009; 19: 29-32
Google Scholar - 50. Muteliefu G., Shimizu H., Enomoto A., Nishijima F., Takahashi M., Niwa T.: Indoxyl sulfate promotes vascular smooth muscle cell senescence with upregulation of p53, p21, and prelamin A through oxidative stress. Am. J. Physiol. Cell Physiol., 2012; 303: C126-C134
Google Scholar - 51. Ng H.Y., Yisireyili M., Saito S., Lee C.T., Adelibieke Y., Nishijima F., Niwa T: Indoxyl sulfate downregulates expression of Mas receptor via OAT3/AhR/Stat3 pathway in proximal tubular cells. PLoS One, 2014; 9: e91517
Google Scholar - 52. Niwa T., Ise M., Miyazaki T.: Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate. Am. J. Nephrol., 1994; 14: 207-212
Google Scholar - 53. Niwa T., Shimizu H.: Indoxyl sulfate induces nephrovascular senescence. J. Ren. Nutr., 2012; 22: 102-106
Google Scholar - 54. Ota H., Akishita M., Tani H., Tatefuji T., Ogawa S., Iijima K., Eto M., Shirasawa T., Ouchi Y.: trans-Resveratrol in Gnetum gnemon protects against oxidative-stress-induced endothelial senescence. J. Nat. Prod., 2013; 76: 1242-1247
Google Scholar - 55. Palm F., Nangaku M., Fasching A., Tanaka T., Nordquist L., Hansell P., Kawakami T., Nishijima F., Fujita T.: Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia of the kidney via oxidative stress. Am. J. Physiol. Renal Physiol., 2010; 299: F380-F386
Google Scholar - 56. Patel R.D., Murray I.A., Flaveny C.A., Kusnadi A., Perdew G.H.: Ah receptor represses acute-phase response gene expression without binding to its cognate response element. Lab. Invest., 2009; 89: 695-707
Google Scholar - 57. Pinheiro S.V., Simões E., Silva A.C.: Angiotensin converting enzyme 2, angiotensin-(1-7), and receptor MAS axis in the kidney. Int. J. Hypertens., 2012; 2012: 414128
Google Scholar - 58. Schmidt J.V., Bradfield C.A.: Ah receptor signaling pathways. Annu. Rev. Cell Dev. Biol., 1996; 12: 55-89
Google Scholar - 59. Schroeder J.C., Dinatale B.C., Murray I.A., Flaveny C.A., Liu Q., Laurenzana E.M., Lin J.M., Strom S.C., Omiecinski C.J., Amin S., Perdew G.H.: The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry, 2010; 49: 393-400
Google Scholar - 60. Shimizu H., Bolati D., Adijiang A., Muteliefu G., Enomoto A., Nishijima F., Dateki M., Niwa T.: NF-κB plays an important role in indoxyl sulfate-induced cellular senescence, fibrotic gene expression, and inhibition of proliferation in proximal tubular cells. Am. J. Physiol. Cell Physiol., 2011; 301: C1201-C1212
Google Scholar - 61. Shimizu H., Saito S., Higashiyama Y., Nishijima F., Niwa T.: CREB, NF-κB, and NADPH oxidase coordinately upregulate indoxyl sulfate- -induced angiotensinogen expression in proximal tubular cells. Am. J. Physiol. Cell Physiol., 2013; 304: C685-C692
Google Scholar - 62. Shivanna S., Kolandaivelu K., Shashar M., Belghasim M., Al- -Rabadi L., Balcells M., Zhang A., Weinberg J., Francis J., Pollastri M.P., Edelman E.R., Sherr D.H., Chitalia V.C.: 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
Google Scholar - 63. Soler M.J., Wysocki J., Batlle D.: ACE2 alterations in kidney disease. Nephrol. Dial. Transplant., 2013; 28: 2687-2697
Google Scholar - 64. Takayama F., Taki K., Niwa T.: Bifidobacterium in gastro-resistant seamless capsule reduces serum levels of indoxyl sulfate in patients on hemodialysis. Am. J. Kidney Dis., 2003; 41 (Suppl. 1): S142-S145
Google Scholar - 65. Tumur Z., Niwa T.: Indoxyl sulfate inhibits nitric oxide production and cell viability by inducing oxidative stress in vascular endothelial cells. Am. J. Nephrol., 2009; 29: 551-557
Google Scholar - 66. Tumur Z., Shimizu H., Enomoto A., Miyazaki H., Niwa T.: Indoxyl sulfate upregulates expression of ICAM-1 and MCP-1 by oxidative stress-induced NF-κB activation. Am. J. Nephrol., 2010; 31: 435-441
Google Scholar - 67. Vanholder R., De Smet R., Glorieux G., Argilés A., Baurmeister U., Brunet P., Clark W., Cohen G., De Deyn P.P., Deppisch R., Descamps- -Latscha B., Henle T., Jörres A., Lemke H.D., Massy Z.A., European Uremic Toxin Work Group: Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int., 2003; 63: 1934-1943
Google Scholar - 68. Veldhoen M., Hirota K., Westendorf A.M., Buer J., Dumoutier L., Renauld J.C., Stockinger B.: The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature, 2008; 453: 106-109
Google Scholar - 69. Walisser J.A., Glover E., Pande K., Liss A.L., Bradfield C.A.: Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proc. Natl. Acad. Sci. USA, 2005; 102: 17858-17863
Google Scholar - 70. Walker M.K., Pollenz R.S., Smith S.M.: Expression of the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator during chick cardiogenesis is consistent with 2,3,7,8-tetrachlorodibenzo- -p-dioxin-induced heart defects. Toxicol. Appl. Pharmacol., 1997; 143: 407-419
Google Scholar - 71. Wang Y.Q., Cao Q., Wang F., Huang L.Y., Sang T.T., Liu F., Chen S.Y.: SIRT1 protects against oxidative stress-induced endothelial progenitor cells apoptosis by inhibiting FOXO3a via FOXO3a ubiquitination and degradation. J. Cell. Physiol., 2015; 230: 2098-2107
Google Scholar - 72. 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
Google Scholar - 73. Wikoff W.R., Anfora A.T., Liu J., Schultz P.G., Lesley S.A., Peters E.C., Siuzdak G.: Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. USA, 2009; 106: 3698-3703
Google Scholar - 74. Yu M., Kim Y.J., Kang D.H.: Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clin. J. Am. Soc. Nephrol., 2011; 6: 30-39
Google Scholar - 75. Zhang S., Qin C., Safe S.H.: Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ. Health Perspect., 2003; 111: 1877-1882
Google Scholar