Hemodialysis Induces p66shc Gene Expression in Nondiabetic Humans: Correlations with Oxidative Stress and Systemic Inflammation

Objective: Oxidative stress and inflammation characterize hemodialysis (HD) and are associated with malnutrition, cardiovascular disease, and poor clinical outcome. p66(shc) stimulates oxidative stress and atherogenesis. The objective of the present study was to assess p66(shc) expression levels in HD and their associations with inflammatory and oxidative stress markers. Design: p66(shc) messenger ribonucleic acid (mRNA) was compared with systemic oxidative stress and inflammation markers in control subjects and patients on HD before and after a single HD session in a cross-sectional analysis. Setting: Outpatient hemodialysis unit. Patients: The study included stable HD patients (n = 21, men/women: 18/3) who were on HD 3 times per week for a minimum of 8 weeks; age-matched control subjects (n = 22, men/women: 17/5). Main Outcome Measure: mRNA levels of p66(shc), tumor necrosis factor alpha (TNF-alpha), and pentraxin 3 (PTX3), p66(shc) protein levels in white blood cells, lipid peroxidation (in the form of plasma thiobarbituric acid-reactive substance [TBARS]) and serum C-reactive protein. Results: In patients on dialysis, of the p66(shc), TNF-alpha, and PTX3 mRNAs, p66(shc) protein levels were higher (P < . 05) than in control subjects, as well as plasma TBARS and C-reactive protein (P < .05). p66(shc) mRNA directly correlated with TBARS (r = 0.69, P = .0005) and with TNF-alpha mRNA (r = 0.63, P = .003). These associations were confirmed in the whole study population (TBARS: r = 0.541, P = .0003; TNF-alpha: r = 0.581, P < . 0001), whereas in the control group only the positive association between p66(shc) and TNF-alpha was detected. TNF-alpha was directly correlated with PTX3 both in HD patients (r = 0.72, P = .0005) and in the whole study group (r = 0.678, P < . 0001). The dialysis session affected neither p66(shc) and TNF-alpha mRNA nor p66(shc) protein expression, whereas it further increased (P < .002) PTX3 mRNA. As compared with predialysis levels, TBARS were reduced (P < .05) after dialysis. In these conditions, p66(shc) remained directly correlated with TNF-alpha (r = 0.901, P < .0001). Conclusions: Increased p66(shc) gene expression correlates with TNF-alpha mRNA and with levels of markers of oxidative stress in HD. We suggest a novel link between HD-associated inflammation and p66(shc) gene expression contributing to systemic oxidative stress. (C) 2011 by the National Kidney Foundation, Inc. All rights reserved.