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.

Metabolic profiles of biological aging in American Indians: The strong heart family study

“…The health effects of free p-Cresol and its conjugates have been inconsistent in previous studies [48, 49]. Here we found that increased level of plasma PCS was associated with longer LTL, suggesting a protective effect on biological aging.…”

Heme Oxygenase-1 and Carbon Monoxide in the Heart

“…The importance of this regulation is evidenced in the Hmox1 −/− mice that exhibit exaggerated injury under similar conditions and likely reflect an inability to modulate inflammation and subsequent repair processes. 93;127-129 Indeed animals lacking HO-1 show elevated mean arterial pressures basally. 130 In contrast, in mice in which HO-1 was selectively over-expressed in the heart, there is improved cardiac function, a reduced number of myocardial infarctions, and an overall reduction in inflammatory and oxidative injury after coronary artery ligation and reperfusion.…”

Antiproliferation effect of the uremic toxin para-cresol on endothelial progenitor cells is related to its antioxidant activity

“…They are reactive species toward oxidation, thus considered to have antioxidant activity. Ujhelyi et al (18) have previously suggested that the decreased antioxidant capacity of plasma ultrafiltrate observed after a hemodialysis session is related to the removal of several protein-bound uremic toxins, including p -cresol. This indicates that phenolic uremic toxins, usually retained in patients with CKD, might have antioxidant activity.…”