title: Hemodialysis reduces inhibitory effect of plasma ultrafiltrate on LDL oxidation and subsequent endothelial reactions.
abstract: Oxidative modification of low-density lipoprotein (LDL) and its deleterious effect on endothelium is implicated in the pathogenesis of atherosclerosis. Endothelium responds to such an insult by upregulating the synthesis of heme oxygenase-1 (HO-1) and ferritin. Endothelial cell damage and dysfunction have been observed in patients with chronic kidney disease (CKD) on maintenance hemodialysis (HD). We studied the effect of low-molecular-weight components of uremic plasma on LDL oxidation and LDL-oxidation-provoked endothelial cell reactions, such as the induction of cytotoxicity and the upregulation of cell-protective HO-1 and ferritin. Plasma ultrafiltrate (molecular weight<5000 Da) from CKD patients on HD or when treated conservatively exhibited a pronounced inhibition on heme-mediated oxidative modification of LDL. Endothelial cell cytotoxicity provoked by LDL oxidation was also attenuated by plasma ultrafiltrate from CKD patients. During HD treatment, a dramatic drop occurred in the retardation of oxidative reactions, and a loss of endothelial cytoprotection exerted by plasma ultrafiltrate was noted. The upregulation of HO-1 and ferritin in response to oxidative stress of LDL was blunted by uremic plasma ultrafiltrate that was released by the end of HD. The decreased antioxidant capacity of ultrafiltrate after HD occurred as a consequence of the intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol. Intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol increases the risk of LDL oxidation and subsequent endothelial cell damage, which underlines the importance of activation of cytoprotective HO-1 and ferritin in endothelium.
authors.affiliation: Department of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Ujhelyi
authors.forename: G
authors.initials: G
authors.lastname: Balla
authors.forename: V
authors.initials: V
authors.lastname: Jeney
authors.forename: Z
authors.initials: Z
authors.lastname: Varga
authors.forename: E
authors.initials: E
authors.lastname: Nagy
authors.forename: G M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: A
authors.initials: A
authors.lastname: Agarwal
authors.forename: J W
authors.initials: JW
authors.lastname: Eaton
authors.forename: J
authors.initials: J
authors.lastname: Balla
mesh_terms: D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000494:pharmacology*; D050197:Atherosclerosis / Q000209:etiology*; D019610:Cytoprotection; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005293:Ferritins / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000235:genetics; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D006435:Renal Dialysis / Q000009:adverse effects*; D014462:Ultrafiltration
chemical_list: D000975:Antioxidants; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D006493:Heparin; D005293:Ferritins; D051547:Heme Oxygenase-1