Advanced oxidation protein products as a novel marker of oxidative stress in uremia

Abstract

Evidence suggests an imbalance between antioxidant and oxidant-generating systems resulting in oxidative stress in uremic patients. As plasma proteins are critical targets for oxidants, we developed a novel spectrophotometric assay which allows to detect advanced oxidation protein products (AOPP) in uremic plasma. By size-exclusion chromatography AOPP are retrieved in two distinct peaks at 600 and below 80 kDa in uremic plasma, while no such peaks are found in control plasma. Further biochemical characterization revealed that AOPP are carried by oxidized plasma proteins, especially albumin and do not have oxidant properties. AOPP increased in a dose-dependent manner following in vitro exposure of plasma or purified human serum albumin (HSA) to hypochlorous acid. Advanced glycation end products of human serum albumin (AGE-HSA) also increased AOPP levels. In vivo, plasma level of AOPP was the highest in patients on hemodialysis, followed by those on peritoneal dialysis and by undialyzed patients with advanced chronic renal failure. AOPP levels correlated with plasma concentrations of dityrosine and AGE-pentosidine, as indices of oxidant-mediated protein damage, but not with thiobarbituric reactive substances as lipid peroxidation markers. A close correlation was also found between AOPP and neopterin levels, suggesting that AOPP could be part in the monocyte-mediated inflammatory disorders associated with uremia. In conclusion, we propose the measurement of AOPP as a reliable marker to estimate the degree of oxidant-mediated protein damage in uremic patients and to predict the potential efficacy of therapeutic strategies aimed at reducing such an oxidative stress.

Advanced oxidation protein products induce pre‐osteoblast apoptosis through a nicotinamide adenine dinucleotide phosphate oxidase‐dependent, mitogen‐activated protein kinases‐mediated intrinsic apoptosis pathway

“…AOPPs play a crucial role in the pathological process of diverse diseases (Kalousova et al., 2002; Witko‐Sarsat et al., 1996, 1998; Xie et al., 2014). Under physiological conditions, plasma AOPP concentration is relatively low while increases with aging (Komosinska‐Vassev et al., 2012; Zhang et al., 2011).…”

“…It was well demonstrated that AOPPs could induce ROS generation via the activation of NADPH oxidase. (Kalousova et al., 2002; Liu et al., 2006; Weinstein & Manolagas, 2000; Witko‐Sarsat et al., 1996; Wu et al., 2016; Xie et al., 2014). We found that AOPPs could activate the NADPH oxidase and significantly increase ROS production in vitro and in vivo.…”

“…AOPPs were prepared according to the procedure described previously (Witko‐Sarsat et al., 1996). In brief, rat serum albumin (RSA, Sigma, St. Louis, MO, USA) solution (20 mg/ml) was incubated with 40 m m hypochlorous acid (Fluke, Buchs, Switzerland) in phosphate‐buffered saline (PBS, pH = 7.4) for 30 min at the room temperature.…”

“…The accumulation of AOPPs is prevalent in diverse redox‐related diseases, such as rheumatoid arthritis (Wu et al., 2016), inflammatory bowel diseases (Xie et al., 2014), diabetes (Kalousova, Skrha & Zima, 2002), chronic kidney disease (Witko‐Sarsat & Descamps‐Latscha, 1997), and postmenopausal osteoporosis (Wu et al., 2015). In addition to being the products of oxidative stress, AOPPs are also inducers of ROS generation (Witko‐Sarsat et al., 1996, 1998). Previous studies have shown that AOPPs can mediate multiple pathogenic processes by inducing a redox‐dependent apoptosis in diverse cells, such as intestine epithelial cells (Xie et al., 2014), podocytes (Zhou et al., 2012), and chondrocytes (Wu et al., 2016; Ye et al., 2017).…”

“…Advanced oxidation protein products (AOPPs) are considered to be biomarkers of oxidant‐mediated protein damage. They are a group of carbonyl‐, dityrosine‐, and pentosidine‐containing protein products generated by reaction of plasma proteins with hypochlorous acid and chloramines during oxidative stress and generally considered to be carried mainly by albumin in the blood circulation (Capeillere‐Blandin, Gausson, Descamps‐Latscha & Witko‐Sarsat, 2004; Marsche et al., 2009; Witko‐Sarsat et al., 1996). The accumulation of AOPPs is prevalent in diverse redox‐related diseases, such as rheumatoid arthritis (Wu et al., 2016), inflammatory bowel diseases (Xie et al., 2014), diabetes (Kalousova, Skrha & Zima, 2002), chronic kidney disease (Witko‐Sarsat & Descamps‐Latscha, 1997), and postmenopausal osteoporosis (Wu et al., 2015).…”