title: Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall.
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.
authors.affiliation: Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium;
authors.forename: Anneleen
authors.initials: A
authors.lastname: Pletinck
authors.forename: Griet
authors.initials: G
authors.lastname: Glorieux
authors.forename: Eva
authors.initials: E
authors.lastname: Schepers
authors.forename: Gerald
authors.initials: G
authors.lastname: Cohen
authors.forename: Bertrand
authors.initials: B
authors.lastname: Gondouin
authors.forename: Maria
authors.initials: M
authors.lastname: Van Landschoot
authors.forename: Sunny
authors.initials: S
authors.lastname: Eloot
authors.forename: Angelique
authors.initials: A
authors.lastname: Rops
authors.forename: Johan
authors.initials: J
authors.lastname: Van de Voorde
authors.forename: An
authors.initials: A
authors.lastname: De Vriese
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
authors.forename: Philippe
authors.initials: P
authors.lastname: Brunet
authors.forename: Wim
authors.initials: W
authors.lastname: Van Biesen
authors.forename: Raymond
authors.initials: R
authors.lastname: Vanholder
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D003408:Cresols / Q000378:metabolism / Q000633:toxicity; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism; D005260:Female; D020719:Glucuronides / Q000378:metabolism / Q000633:toxicity; D006439:Hemodynamics / Q000276:immunology; D007200:Indican / Q000378:metabolism / Q000633:toxicity; D036904:Leukocyte Rolling / Q000276:immunology; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D010537:Peritoneum / Q000098:blood supply; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000276:immunology* / Q000378:metabolism*; D016897:Respiratory Burst / Q000276:immunology; D013463:Sulfuric Acid Esters / Q000378:metabolism / Q000633:toxicity; D014511:Uremia / Q000276:immunology* / Q000378:metabolism*
chemical_list: C485699:4-cresylglucuronide; D003408:Cresols; D020719:Glucuronides; D008070:Lipopolysaccharides; D013463:Sulfuric Acid Esters; C408690:4-cresol sulfate; D007200:Indican