Advanced oxidation protein products as a novel molecular basis of oxidative stress in uraemia.

status in chronic renal failure. Indeed, we described Oxidative stress in uraemia syndrome for the first time, the presence in the plasma of haemodialysed patients high levels of oxidized proteins that Considerable evidence has accumulated that chronic we designated AOPPs [11]. Since oxidative damage to uraemia is associated with a multifactorial immunoproteins modifies the spectroscopic characteristics of inflammatory syndrome, which occurs early in the proteins, for example through the oxidation of arocourse of renal failure, is accentuated with the progresmatic amino acid residues, we studied spectral characsion of uraemia and culminates in maintenance dialysis teristics in plasma fractionated by size exclusion therapy [1,2]. Besides the dysregulation in the balance chromatography. We pointed out two UV-visible peaks between pro-inflammatory cytokines and their inhibof absorbance at 340 nm in plasma from haemodiaitors which has been described in uraemic patients lysed patients which were absent in controls. These [3,4], a disturbance in the balance between oxidants two peaks, corresponding to a molecular mass of 60 and antioxidants has also been pointed out. The and 600 kDa, were called low molecular weighthaemodialysis setting could be considered as a human (LMW ) and high molecular weight(HMW ) AOPPs, model of oxidative stress since blood–dialyser interrespectively. action triggers circulating neutrophils to produce a Interestingly, formation of AOPPs could be induced large amount of reactive oxygen species, including in control plasma by chlorinated oxidants such as superoxide anion, hydrogen peroxide, hydroxyl radical, chloramines or hypochlorous acid. Of note, the in vitro and hypochlorous acid [5,6 ] which are partially scavformation of AOPPs was much lower when proteins enged by plasma components. However, due to a were submitted to 22 compared to identical concenprofound deficiency in antioxidant systems, this scavtrations of chlorinated oxidants. Moreover, the formaenging potential is likely to be overwhelmed and tion of AOPPs using purified human serum albumin chronic oxidative stress will thus take place [7,8]. was clearly correlated to the concentration of chlorinMoreover, one of the features of uraemia is the presated oxidant added, thus demonstrating that AOPP ence of signs of oxidative stress before haemodialysis, resulted from the interaction between such oxidants thus emphasizing the importance of evaluating the and plasma proteins. physiopathological role of oxidative stress with respect The HMW-AOPPs generated in plasma from to the uraemia-related immune dysregulation and haemodialysed patients suggested that they were crossinflammatory processes. linking products. Since glycation-modified proteins also induced protein cross-linking and are elevated in uraemic patients [12,13], we studied the relationships Description of advanced oxidation protein products between AOPPs and advanced glycation end product(AOPPs) (AGEs) pentosidine, considered as a marker of protein glycation, and showed that AOPPs and AGEs were highly correlated. Moreover, AOPPs were highly corMeasurement of oxidative stress is not straightforward related with dityrosine, a marker of protein oxidation and standardized methods are still lacking. In our [14]. Interestingly, recent work has demonstrated that search for oxidative stress markers relevant to uraemia, biochemical reactions of protein glycation involve oxidwe investigated the possibility that oxidants could ative pathways, which is of great relevance in the induce oxidative damage to plasma proteins [9,10]. uraemic syndrome [15]. Although proteins are elective targets of oxidants, no clinical studies have been performed to quantify oxidant-induced protein damage in relation to clinical Biological activity of AOPPs