Abstract
Chronic kidney disease (CKD) is associated with high risk of thrombosis. Indole-3 acetic acid (IAA), an indolic uremic toxin, induces the expression of tissue factor (TF) in human umbilical vein endothelial cells (HUVEC) via the transcription factor aryl hydrocarbon receptor (AhR). This study aimed to understand the signaling pathways involved in AhR-mediated TF induction by IAA. We incubated human endothelial cells with IAA at 50 µM, the maximal concentration found in patients with CKD. IAA induced TF expression in different types of human endothelial cells: umbilical vein (HUVEC), aortic (HAoEC), and cardiac-derived microvascular (HMVEC-C). Using AhR inhibition and chromatin immunoprecipitation experiments, we showed that TF induction by IAA in HUVEC was controlled by AhR and that AhR did not bind to the TF promoter. The analysis of TF promoter activity using luciferase reporter plasmids showed that the NF-κB site was essential in TF induction by IAA. In addition, TF induction by IAA was drastically decreased by an inhibitor of the NF-κB pathway. IAA induced the nuclear translocation of NF-κB p50 subunit, which was decreased by AhR and p38MAPK inhibition. Finally, in a cohort of 92 CKD patients on hemodialysis, circulating TF was independently related to serum IAA in multivariate analysis. In conclusion, TF up-regulation by IAA in human endothelial cells involves a non-genomic AhR/p38 MAPK/NF-κB pathway. The understanding of signal transduction pathways related to AhR thrombotic/inflammatory pathway is of interest to find therapeutic targets to reduce TF expression and thrombotic risk in patients with CKD.
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References
Ahern SM, Miyata T, Sadler JE (1993) Regulation of human tissue factor expression by mRNA turnover. J Biol Chem 268:2154–2159
Armstead VE, Opentanova IL, Minchenko AG, Lefer AM (1999) Tissue factor expression in vital organs during murine traumatic shock: role of transcription factors AP-1 and NF-kappaB. Anesthesiology 91:1844–1852. https://doi.org/10.1097/00000542-199912000-00039
Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M, Choukroun G, Vanholder R, Massy ZA, Group (EUTox) on behalf of the EUTW (2009) Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. CJASN 4:1551–1558. https://doi.org/10.2215/CJN.03980609
Bode M, Mackman N (2014) Regulation of tissue factor gene expression in monocytes and endothelial cells: thromboxane A2 as a new player. Vascul Pharmacol 62:57–62. https://doi.org/10.1016/j.vph.2014.05.005
Borlak J, Jenke HS (2008) Cross-talk between aryl hydrocarbon receptor and mitogen-activated protein kinase signaling pathway in liver cancer through c-raf transcriptional regulation. Mol Cancer Res 6:1326–1336. https://doi.org/10.1158/1541-7786.MCR-08-0042
Brand K, Fowler BJ, Edgington TS, Mackman N (1991) Tissue factor mRNA in THP-1 monocytic cells is regulated at both transcriptional and posttranscriptional levels in response to lipopolysaccharide. Mol Cell Biol 11:4732–4738
Calaf R, Cerini C, Génovésio C, Verhaeghe P, Jourde-Chiche N, Bergé-Lefranc D, Gondouin B, Dou L, Morange S, Argilés A, Rathelot P, Dignat-George F, Brunet P, Charpiot P (2011) Determination of uremic solutes in biological fluids of chronic kidney disease patients by HPLC assay. J Chromatogr B Anal Technol Biomed Life Sci 879:2281–2286. https://doi.org/10.1016/j.jchromb.2011.06.014
Camerer E, Kolstø AB, Prydz H (1996) Cell biology of tissue factor, the principal initiator of blood coagulation. Thromb Res 81:1–41
Carney EF (2016) Thrombosis: new mechanism of thrombus formation in CKD. Nat Rev Nephrol 12:715. https://doi.org/10.1038/nrneph.2016.155
Chitalia VC, Shivanna S, Martorell J, Balcells M, Bosch I, Kolandaivelu K, Edelman ER (2013) Uremic serum and solutes increase post-vascular interventional thrombotic risk through altered stability of smooth muscle cell tissue factor. Circulation 127:365–376. https://doi.org/10.1161/CIRCULATIONAHA.112.118174
Crossman DC, Carr DP, Tuddenham EG, Pearson JD, McVey JH (1990) The regulation of tissue factor mRNA in human endothelial cells in response to endotoxin or phorbol ester. J Biol Chem 265:9782–9787
Daneschvar HL, Seddighzadeh A, Piazza G, Goldhaber SZ (2008) Deep vein thrombosis in patients with chronic kidney disease. Thromb Haemost 99:1035–1039. https://doi.org/10.1160/TH08-02-0107
Di Meglio P, Duarte JH, Ahlfors H, Owens NDL, Li Y, Villanova F, Tosi I, Hirota K, Nestle FO, Mrowietz U, Gilchrist MJ, Stockinger B (2014) Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity 40:989–1001. https://doi.org/10.1016/j.immuni.2014.04.019
Dolwick KM, Swanson HI, Bradfield CA (1993) In vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition. Proc Natl Acad Sci USA 90:8566–8570
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 (2015) The cardiovascular effect of the uremic solute indole-3 acetic acid. J Am Soc Nephrol 26:876–887. https://doi.org/10.1681/ASN.2013121283
Dou L, Poitevin S, Sallée M, Addi T, Gondouin B, McKay N, Denison MS, Jourde-Chiche N, Duval-Sabatier A, Cerini C, Brunet P, Dignat-George F, Burtey S (2018) Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. Kidney Int 93:986–999. https://doi.org/10.1016/j.kint.2017.11.010
Fernandez-Prado R, Esteras R, Perez-Gomez MV, Gracia-Iguacel C, Gonzalez-Parra E, Sanz AB, Ortiz A, Sanchez-Niño MD (2017) Nutrients turned into toxins: microbiota modulation of nutrient properties in chronic kidney disease. Nutrients. https://doi.org/10.3390/nu9050489
Fujii-Kuriyama Y, Mimura J (2005) Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochem Biophys Res Commun 338:311–317. https://doi.org/10.1016/j.bbrc.2005.08.162
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351:1296–1305. https://doi.org/10.1056/NEJMoa041031
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 (2013) Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. Kidney Int 84:733–744. https://doi.org/10.1038/ki.2013.133
Han H, Zhu J, Zhu Z, Ni J, Du R, Dai Y, Chen Y, Wu Z, Lu L, Zhang R (2015) p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes. J Am Heart Assoc 4:e001852. https://doi.org/10.1161/JAHA.115.001852
Hankinson O (1995) The Aryl Hydrocarbon Receptor Complex. Annu Rev Pharmacol Toxicol 35:307–340. https://doi.org/10.1146/annurev.pa.35.040195.001515
Heath-Pagliuso S, Rogers WJ, Tullis K, Seidel SD, Cenijn PH, Brouwer A, Denison MS (1998) Activation of the Ah receptor by tryptophan and tryptophan metabolites. Biochemistry 37:11508–11515. https://doi.org/10.1021/bi980087p
Heid SE, Pollenz RS, Swanson HI (2000) Role of heat shock protein 90 dissociation in mediating agonist-induced activation of the aryl hydrocarbon receptor. Mol Pharmacol 57:82–92
Henklová P, Vrzal R, Ulrichová J, Dvorák Z (2008) Role of mitogen-activated protein kinases in aryl hydrocarbon receptor signaling. Chem Biol Interact 172:93–104. https://doi.org/10.1016/j.cbi.2007.12.005
Huang G, Elferink CJ (2012) A novel nonconsensus xenobiotic response element capable of mediating aryl hydrocarbon receptor-dependent gene expression. Mol Pharmacol 81:338–347. https://doi.org/10.1124/mol.111.075952
Huang M-J, Wei R-B, Wang Y, Su T-Y, Di P, Li Q-P, Yang X, Li P, Chen X-M (2017) Blood coagulation system in patients with chronic kidney disease: a prospective observational study. BMJ Open 7:e014294. https://doi.org/10.1136/bmjopen-2016-014294
Ito S, Osaka M, Edamatsu T, Itoh Y, Yoshida M (2016) Crucial role of the aryl hydrocarbon receptor (AhR) in indoxyl sulfate-induced vascular inflammation. J Atheroscler Thromb 23:960–975. https://doi.org/10.5551/jat.34462
Jackson DP, Li H, Mitchell KA, Joshi AD, Elferink CJ (2014) Ah receptor-mediated suppression of liver regeneration through NC-XRE-driven p21Cip1 expression. Mol Pharmacol 85:533–541. https://doi.org/10.1124/mol.113.089730
Jackson DP, Joshi AD, Elferink CJ (2015) Ah receptor pathway intricacies; signaling through diverse protein partners and DNA-motifs. Toxicol Res (Camb) 4:1143–1158
Jaffe EA, Nachman RL, Becker CG, Minick CR (1973) Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 52:2745–2756. https://doi.org/10.1172/JCI107470
Jalal DI, Chonchol M, Targher G (2010) Disorders of hemostasis associated with chronic kidney disease. Semin Thromb Hemost 36:34–40. https://doi.org/10.1055/s-0030-1248722
Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Vanholder R, Brunet P (2009) Protein-bound toxins–update 2009. Semin Dial 22:334–339. https://doi.org/10.1111/j.1525-139X.2009.00576.x
Kim S-H, Henry EC, Kim D-K, Kim Y-H, Shin KJ, Han MS, Lee TG, Kang J-K, Gasiewicz TA, Ryu SH, Suh P-G (2006) Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol 69:1871–1878. https://doi.org/10.1124/mol.105.021832
Kim MJ, Pelloux V, Guyot E, Tordjman J, Bui L-C, Chevallier A, Forest C, Benelli C, Clément K, Barouki R (2012) Inflammatory pathway genes belong to major targets of persistent organic pollutants in adipose cells. Environ Health Perspect 120:508–514. https://doi.org/10.1289/ehp.1104282
Li Y-D, Ye B-Q, Zheng S-X, Wang J-T, Wang J-G, Chen M, Liu J-G, Pei X-H, Wang L-J, Lin Z-X, Gupta K, Mackman N, Slungaard A, Key NS, Geng J-G (2009) NF-kappaB transcription factor p50 critically regulates tissue factor in deep vein thrombosis. J Biol Chem 284:4473–4483. https://doi.org/10.1074/jbc.M806010200
Lim PS, Sutton CR, Rao S (2015) Protein kinase C in the immune system: from signalling to chromatin regulation. Immunology 146:508–522. https://doi.org/10.1111/imm.12510
Ma C, Marlowe JL, Puga A (2009) The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways. In: Molecular, clinical and environmental toxicology. Birkhäuser, Basel, pp 231–257
Mackman N, Brand K, Edgington TS (1991) Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor kappa B binding sites. J Exp Med 174:1517–1526
Mandal PK (2005) Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J Comp Physiol B 175:221–230. https://doi.org/10.1007/s00360-005-0483-3
Matsumura F (2009) The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects. Biochem Pharmacol 77:608–626. https://doi.org/10.1016/j.bcp.2008.10.013
Moradi H, Sica DA, Kalantar-Zadeh K (2013) Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease. Am J Nephrol 38:136–148. https://doi.org/10.1159/000351758
Neirynck N, Glorieux G, Schepers E, Pletinck A, Dhondt A, Vanholder R (2013) Review of protein-bound toxins, possibility for blood purification therapy. Blood Purif 35(Suppl 1):45–50. https://doi.org/10.1159/000346223
Oeth P, Parry GC, Mackman N (1997) Regulation of the tissue factor gene in human monocytic cells. Role of AP-1, NF-kappa B/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression. Arterioscler Thromb Vasc Biol 17:365–374
Øvrevik J, Låg M, Lecureur V, Gilot D, Lagadic-Gossmann D, Refsnes M, Schwarze PE, Skuland T, Becher R, Holme JA (2014) AhR and Arnt differentially regulate NF-κB signaling and chemokine responses in human bronchial epithelial cells. Cell Commun Signal 12:48. https://doi.org/10.1186/s12964-014-0048-8
Parry GC, Mackman N (1995) Transcriptional regulation of tissue factor expression in human endothelial cells. Arterioscler Thromb Vasc Biol 15:612–621
Pawlak K, Mysliwiec M, Pawlak D (2009) Hypercoagulability is independently associated with kynurenine pathway activation in dialysed uraemic patients. Thromb Haemost 102:49–55. https://doi.org/10.1160/TH08-10-0696
Petrulis JR, Perdew GH (2002) The role of chaperone proteins in the aryl hydrocarbon receptor core complex. Chem Biol Interact 141:25–40
Puga A, Ma C, Marlowe JL (2009a) The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochem Pharmacol 77:713–722. https://doi.org/10.1016/j.bcp.2008.08.031
Puga A, Ma C, Marlowe JL (2009b) The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochem Pharmacol 77:713. https://doi.org/10.1016/j.bcp.2008.08.031
Reddy KV, Bhattacharjee G, Schabbauer G, Hollis A, Kempf K, Tencati M, O’Connell M, Guha M, Mackman N (2004) Dexamethasone enhances LPS induction of tissue factor expression in human monocytic cells by increasing tissue factor mRNA stability. J Leukoc Biol 76:145–151. https://doi.org/10.1189/jlb.0204068
Sallée M, Dou L, Cerini C, Poitevin S, Brunet P, Burtey S (2014) The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease. Toxins 6:934–949. https://doi.org/10.3390/toxins6030934
Sciullo EM, Vogel CF, Li W, Matsumura F (2008) Initial and extended inflammatory messages of the nongenomic signaling pathway of the TCDD-activated Ah receptor in U937 macrophages. Arch Biochem Biophys 480:143–155. https://doi.org/10.1016/j.abb.2008.09.017
Serradell M, Díaz-Ricart M, Cases A, Zurbano MJ, Aznar-Salatti J, López-Pedret J, Ordinas A, Escolar G (2001) Uremic medium disturbs the hemostatic balance of cultured human endothelial cells. Thromb Haemost 86:1099–1105
Shashar M, Belghasem ME, Matsuura S, Walker J, Richards S, Alousi F, Rijal K, Kolachalama VB, Balcells M, Odagi M, Nagasawa K, Henderson JM, Gautam A, Rushmore R, Francis J, Kirchhofer D, Kolandaivelu K, Sherr DH, Edelman ER, Ravid K, Chitalia VC (2017) Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aam8475
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 (2016) The aryl hydrocarbon receptor is a critical regulator of tissue factor stability and an antithrombotic target in Uremia. J Am Soc Nephrol 27:189–201. https://doi.org/10.1681/ASN.2014121241
Storino G, Moraes C, Saldanha J, Mafra D (2015) Cardiovascular mortality in chronic kidney patients: the role of uremic toxins. Int J Cardiovasc Sci 28:327–334. https://doi.org/10.5935/2359-4802.20150047
Swanson HI, Chan WK, Bradfield CA (1995) DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins. J Biol Chem 270:26292–26302
Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg AX (2006) Chronic kidney disease and mortality risk: a systematic review. JASN 17:2034–2047. https://doi.org/10.1681/ASN.2005101085
Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jörres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W, European Uremic Toxin Work Group (EUTox) (2003) Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 63:1934–1943. https://doi.org/10.1046/j.1523-1755.2003.00924.x
Vogel CFA, Matsumura F (2009) A new cross-talk between the Aryl hydrocarbon receptor and RelB, a member of the NF-κB family. Biochem Pharmacol 77:734–745. https://doi.org/10.1016/j.bcp.2008.09.036
Vogel CFA, Li W, Wu D, Miller JK, Sweeney C, Lazennec G, Fujisawa Y, Matsumura F (2011) Interaction of Aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with Interleukin-8 overexpression. Arch Biochem Biophys 512:78–86. https://doi.org/10.1016/j.abb.2011.05.011
Wattanakit K, Cushman M (2009) Chronic kidney disease and venous thromboembolism: epidemiology and mechanisms. Curr Opin Pulm Med 15:408–412. https://doi.org/10.1097/MCP.0b013e32832ee371
Xia L, Zhou H, Hu L, Xie H, Wang T, Xu Y, Liu J, Zhang X, Yan J (2013) Both NF-κB and c-Jun/AP-1 involved in anti-β2GPI/β2GPI-induced tissue factor expression in monocytes. Thromb Haemost 109:643–651. https://doi.org/10.1160/TH12-09-0655
Xia L, Xie H, Yu Y, Zhou H, Wang T, Yan J (2016) The effects of NF-κB and c-Jun/AP-1 on the expression of prothrombotic and proinflammatory molecules induced by anti-β2GPI in mouse. PLoS One 11:e0147958. https://doi.org/10.1371/journal.pone.0147958
Zhao D, Pritts EA, Chao VA, Savouret J-F, Taylor RN (2002) Dioxin stimulates RANTES expression in an in-vitro model of endometriosis. Mol Hum Reprod 8:849–854
Acknowledgements
This work was supported by funding from the Aix-Marseille University, the Institut National de la santé et de la Recherche médicale (INSERM), the European Uremic Toxins (EUTox) Work Group, the University of Oran 1 Ahmed Benbella, and the Algerian Ministry of Higher Education and Scientific Research. We thank K. Fallague and C. Scagliarini for technical assistance.
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Addi, T., Poitevin, S., McKay, N. et al. Mechanisms of tissue factor induction by the uremic toxin indole-3 acetic acid through aryl hydrocarbon receptor/nuclear factor-kappa B signaling pathway in human endothelial cells. Arch Toxicol 93, 121–136 (2019). https://doi.org/10.1007/s00204-018-2328-3
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DOI: https://doi.org/10.1007/s00204-018-2328-3