Abstract
Plasma advanced oxidation protein products (AOPPs), a class of pro-inflammatory pathogenic mediators, accumulate in subjects with chronic kidney disease. Whether AOPPs contribute to coagulation abnormalities, which are frequently seen in uremic patients, is unknown. Here we report that AOPPs activate platelets via a CD36-mediated signaling pathway. Activation of signaling pathways by AOPP-platelet interaction resulted in the expression of several platelet activation markers and rapidly induced the expression of CD40 ligand, triggering platelet adhesion to endothelial cells and promoting endothelial tissue factor expression. AOPPs and serum tissue factor levels were considerably increased in end stage renal disease patients on hemodialysis and a significant correlation of AOPPs and serum tissue factor was found. Interestingly, serum levels of AOPPs and tissue factor were substantially lower in stable kidney transplant patients when compared with hemodialysis patients. Given that CD36 is known to transduce the effects of oxidized lipids into platelet hyperactivity, our findings reveal previously unknown pro-thrombotic activities of oxidized plasma albumin via a CD36 dependent pathway.
Highlights
We provide evidence that advanced oxidation protein products (AOPPs)-albumin isolated from end stage renal disease patients as well as in vitro generated AOPPs markedly increase ADP-induced platelet aggregation via CD36
Our results suggest that AOPPs activate phospholipase C (PLC), which catalyzes the hydrolysis of phosphatidyl inositol 4, 5 bisphosphate to inositol triphosphate (IP3) and diacylglycerol
Previous studies demonstrated that AOPPs activate NAD(P)H oxidase through a protein kinase C (PKC) dependent pathway and promote reactive oxygen species (ROS) production in various cell types[8,28,33]
Summary
Serum AOPP levels were markedly higher in end stage renal disease patients on hemodialysis (HD) when compared with healthy controls (Fig. 5a). In good agreement with results above, AOPP-albumin isolated from uremic patients promoted ADP induced platelet aggregation dependent on AOPP levels (Fig. 5b). Tissue factor levels were profoundly increased in end stage renal disease patients on HD whereas kidney transplant patients showed levels was dissolved in DMSO, effects of BAPTA-AM were compared to AOPPs induced response in the presence of DMSO (n = 3–5).
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