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Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway

(2013) KIDNEY INTERNATIONAL. 84(4). p.733-744
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Abstract
In chronic kidney disease (CKD), uremic solutes accumulate in blood and tissues. These compounds probably contribute to the marked increase in cardiovascular risk during the progression of CKD. The uremic solutes indoxyl sulfate and indole-3-acetic acid (IAA) are particularly deleterious for endothelial cells. Here we performed microarray and comparative PCR analyses to identify genes in endothelial cells targeted by these two uremic solutes. We found an increase in endothelial expression of tissue factor in response to indoxyl sulfate and IAA and upregulation of eight genes regulated by the transcription factor aryl hydrocarbon receptor (AHR). The suggestion by microarray analysis of an involvement of AHR in tissue factor production was confirmed by siRNA inhibition and the indirect AHR inhibitor geldanamycin. These observations were extended to peripheral blood mononuclear cells. Tissue factor expression and activity were also increased by AHR agonist dioxin. Finally, we measured circulating tissue factor concentration and activity in healthy control subjects and in patients with CKD (stages 3-5d), and found that each was elevated in patients with CKD. Circulating tissue factor levels were positively correlated with plasma indoxyl sulfate and IAA. Thus, indolic uremic solutes increase tissue factor production in endothelial and peripheral blood mononuclear cells by AHR activation, evoking a 'dioxin-like' effect. This newly described mechanism of uremic solute toxicity may help understand the high cardiovascular risk of CKD patients.
Keywords
CHRONIC KIDNEY-DISEASE, FACTOR UP-REGULATION, uremic solutes, tissue factor, aryl hydrocarbon receptor, FACTOR EXPRESSION, OXIDATIVE STRESS, CARDIOVASCULAR-DISEASES, HEMODIALYSIS-PATIENTS, RESPONSE ELEMENT, GENE-EXPRESSION, ACTIVATION, INFLAMMATION

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Citation

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Chicago
Gondouin, Bertrand, Claire Cerini, Laetitia Dou, Marion Sallée, Ariane Duval-Sabatier, Anneleen Pletinck, Raymond Calaf, et al. 2013. “Indolic Uremic Solutes Increase Tissue Factor Production in Endothelial Cells by the Aryl Hydrocarbon Receptor Pathway.” Kidney International 84 (4): 733–744.
APA
Gondouin, Bertrand, Cerini, C., Dou, L., Sallée, M., Duval-Sabatier, A., Pletinck, A., Calaf, R., et al. (2013). Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. KIDNEY INTERNATIONAL, 84(4), 733–744.
Vancouver
1.
Gondouin B, Cerini C, Dou L, Sallée M, Duval-Sabatier A, Pletinck A, et al. Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. KIDNEY INTERNATIONAL. 2013;84(4):733–44.
MLA
Gondouin, Bertrand, Claire Cerini, Laetitia Dou, et al. “Indolic Uremic Solutes Increase Tissue Factor Production in Endothelial Cells by the Aryl Hydrocarbon Receptor Pathway.” KIDNEY INTERNATIONAL 84.4 (2013): 733–744. Print.
@article{4217060,
  abstract     = {In chronic kidney disease (CKD), uremic solutes accumulate in blood and tissues. These compounds probably contribute to the marked increase in cardiovascular risk during the progression of CKD. The uremic solutes indoxyl sulfate and indole-3-acetic acid (IAA) are particularly deleterious for endothelial cells. Here we performed microarray and comparative PCR analyses to identify genes in endothelial cells targeted by these two uremic solutes. We found an increase in endothelial expression of tissue factor in response to indoxyl sulfate and IAA and upregulation of eight genes regulated by the transcription factor aryl hydrocarbon receptor (AHR). The suggestion by microarray analysis of an involvement of AHR in tissue factor production was confirmed by siRNA inhibition and the indirect AHR inhibitor geldanamycin. These observations were extended to peripheral blood mononuclear cells. Tissue factor expression and activity were also increased by AHR agonist dioxin. Finally, we measured circulating tissue factor concentration and activity in healthy control subjects and in patients with CKD (stages 3-5d), and found that each was elevated in patients with CKD. Circulating tissue factor levels were positively correlated with plasma indoxyl sulfate and IAA. Thus, indolic uremic solutes increase tissue factor production in endothelial and peripheral blood mononuclear cells by AHR activation, evoking a 'dioxin-like' effect. This newly described mechanism of uremic solute toxicity may help understand the high cardiovascular risk of CKD patients.},
  author       = {Gondouin, Bertrand and Cerini, Claire and Dou, Laetitia and Sallée, Marion and Duval-Sabatier, Ariane and Pletinck, Anneleen and Calaf, Raymond and Lacroix, Romanic and Jourde-Chiche, Noémie and Poitevin, Stéphane and Arnaud, Laurent and Vanholder, Raymond and Brunet, Philippe and Dignat-George, Fran§oise and Burtey, Stéphane},
  issn         = {0085-2538},
  journal      = {KIDNEY INTERNATIONAL},
  keywords     = {CHRONIC KIDNEY-DISEASE,FACTOR UP-REGULATION,uremic solutes,tissue factor,aryl hydrocarbon receptor,FACTOR EXPRESSION,OXIDATIVE STRESS,CARDIOVASCULAR-DISEASES,HEMODIALYSIS-PATIENTS,RESPONSE ELEMENT,GENE-EXPRESSION,ACTIVATION,INFLAMMATION},
  language     = {eng},
  number       = {4},
  pages        = {733--744},
  title        = {Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway},
  url          = {http://dx.doi.org/10.1038/ki.2013.133},
  volume       = {84},
  year         = {2013},
}

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