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Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall

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Abstract
Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD. Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses and cardiovascular damage, corroborating observational in vivo data. However, the impact of these uremic toxins on the crosstalk between endothelium and leukocytes has not been assessed. This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG) on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. Superfusion with IS induced strong leukocyte adhesion, enhanced extravasation, and interrupted blood flow, whereas pCS caused a rapid increase in leukocyte rolling. Superfusion with pCS and pCG combined caused impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over pCS alone. Intravenous infusion with IS confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating IS-induced flow stagnation. These results provide the first clear in vivo evidence that IS, pCS, and pCG exert proinflammatory effects that contribute to vascular damage by stimulating crosstalk between leukocytes and vessels.
Keywords
FREE P-CRESOL, CHRONIC-RENAL-FAILURE, INDOXYL SULFATE, HEMODIALYSIS-PATIENTS, HEPARAN-SULFATE, CARDIOVASCULAR-DISEASE, OXIDATIVE STRESS, IN-VIVO, GLOMERULAR ENDOTHELIAL-CELLS, CHRONIC KIDNEY-DISEASE

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Chicago
Pletinck, Anneleen, Griet Glorieux, Eva Schepers, Gerald Cohen, Bertrand Gondouin, Maria Van Landschoot, Sunny Eloot, et al. 2013. “Protein-bound Uremic Toxins Stimulate Crosstalk Between Leukocytes and Vessel Wall.” Journal of the American Society of Nephrology 24 (12): 1981–1994.
APA
Pletinck, A., Glorieux, G., Schepers, E., Cohen, G., Gondouin, B., Van Landschoot, M., Eloot, S., et al. (2013). Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 24(12), 1981–1994.
Vancouver
1.
Pletinck A, Glorieux G, Schepers E, Cohen G, Gondouin B, Van Landschoot M, et al. Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. 2013;24(12):1981–94.
MLA
Pletinck, Anneleen, Griet Glorieux, Eva Schepers, et al. “Protein-bound Uremic Toxins Stimulate Crosstalk Between Leukocytes and Vessel Wall.” JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 24.12 (2013): 1981–1994. Print.
@article{4267941,
  abstract     = {Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD. Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses and cardiovascular damage, corroborating observational in vivo data. However, the impact of these uremic toxins on the crosstalk between endothelium and leukocytes has not been assessed. This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG) on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. Superfusion with IS induced strong leukocyte adhesion, enhanced extravasation, and interrupted blood flow, whereas pCS caused a rapid increase in leukocyte rolling. Superfusion with pCS and pCG combined caused impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over pCS alone. Intravenous infusion with IS confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating IS-induced flow stagnation. These results provide the first clear in vivo evidence that IS, pCS, and pCG exert proinflammatory effects that contribute to vascular damage by stimulating crosstalk between leukocytes and vessels.},
  author       = {Pletinck, Anneleen and Glorieux, Griet and Schepers, Eva and Cohen, Gerald and Gondouin, Bertrand and Van Landschoot, Maria and Eloot, Sunny and Rops, Angelique and Van de Voorde, Johan and De Vriese, An and van der Vlag, Johan and Brunet, Philippe and Van Biesen, Wim and Vanholder, Raymond},
  issn         = {1046-6673},
  journal      = {JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY},
  keyword      = {FREE P-CRESOL,CHRONIC-RENAL-FAILURE,INDOXYL SULFATE,HEMODIALYSIS-PATIENTS,HEPARAN-SULFATE,CARDIOVASCULAR-DISEASE,OXIDATIVE STRESS,IN-VIVO,GLOMERULAR ENDOTHELIAL-CELLS,CHRONIC KIDNEY-DISEASE},
  language     = {eng},
  number       = {12},
  pages        = {1981--1994},
  title        = {Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall},
  url          = {http://dx.doi.org/10.1681/ASN.2012030281},
  volume       = {24},
  year         = {2013},
}

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