title: Para-cresyl sulfate acutely impairs vascular reactivity and induces vascular remodeling.
abstract: Chronic kidney disease (CKD) is characterized by vascular remodeling and the retention of uremic toxins, several of which are independently associated with the high cardiovascular mortality rate in CKD patients. Whether the association between these uremic toxins and cardiovascular mortality is due to induction of vascular dysfunction and resulting vascular remodeling remains to be determined. This study evaluates the effects of para-cresyl sulfate (PCS), a newly identified uremic toxin, on vascular function and remodeling. PCS acutely induced oxidative stress in both endothelial and vascular smooth muscle cells, with a maximal effect at 0.15 mM, corresponding to the mean "uremic" concentration found in dialysis patients. PCS significantly increased within 30 min phenylephrine-induced contraction of mouse thoracic aorta, through direct activation of rho-kinase, independently of oxidative stress induction, as demonstrated by the capacity of rho-kinase inhibitor Y-27632 to abolish this effect. After exposure of the aorta to PCS for 48 h, we observed inward eutrophic remodeling, a hallmark of uremic vasculopathy characterized by a reduction of the area of both lumen and media, with unchanged media/lumen ratio. In conclusion, elevated PCS concentrations such as those observed in CKD patients, by promoting both vascular dysfunction and vascular remodeling, may contribute to the development of hypertension and to cardiovascular mortality in CKD.
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Gross
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.|Division of Nephrology, Ambroise Paré University Hospital, AP-HP, Paris-Ile-de-France-Ouest University (UVSQ), Boulogne-Billancourt, France.
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Henaut
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Boudot
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Cagnard
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Cécilia
authors.initials: C
authors.lastname: March
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Saïd
authors.initials: S
authors.lastname: Kamel
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Tilman B
authors.initials: TB
authors.lastname: Drueke
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Six
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D003408:Cresols / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013463:Sulfuric Acid Esters / Q000633:toxicity*; D013997:Time Factors; D046509:Tissue Culture Techniques; D066253:Vascular Remodeling / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D003408:Cresols; D013463:Sulfuric Acid Esters; C408690:4-cresol sulfate; D054460:rho-Associated Kinases