Dinucleoside polyphosphates: Newly detected uraemic compounds with an impact on leucocyte oxidative burst

Abstract

Background. Dinucleoside polyphosphates (NpnN) have pathophysiologic roles in cardiovascular disease and are newly detected uraemic retention solutes. They were retrieved in human plasma, tissues and cells. Although their impact on several cell systems involved in vascular damage (endothelium, smooth muscle cells and thrombocytes) has been evaluated, their effect on different types of leucocytes has never been studied.Methods. This study evaluates, for the first time, the impact of NpnN on monocyte, granulocyte and lymphocyte oxidative burst activity at baseline and after stimulation with N-formyl-methionine-leucine- phenylalanine (fMLP) and phorbol 12-myristate 13-acetate (PMA) in whole blood. Diadenosine triphosphate (Ap3A) to diadenosine hexaphosphate (Ap6A) were tested to investigate the effect of the number of phosphate groups on reactive oxygen species (ROS) production. The effect of the type of nucleoside was evaluated by comparing adenosine guanosine tetraphosphate, diguanosine tetraphosphate, uridine adenosine tetraphosphate (Up4A) and diadenosine tetraphosphate (Ap4A).Results. This study demonstrated that lymphocytes are especially susceptible to intracellular diadenosine polyphosphates. Depending on the phosphate chain length, different effects were observed. At baseline and with fMLP, Ap4A, Ap5A and Ap6A enhanced lymphocyted-free radical production. In addition, Ap3A, Ap4A and Ap5A increased PMA-stimulated ROS production in lymphocytes. Monocytes and granulocytes parallel the lymphocyte response albeit with an inhibition of Ap6A on granulocytes. Considering NpnN with four phosphate groups, Up4A showed the most important stimulatory effects on monocytes and Ap4A on lymphocytes.Conclusions. NpnN mainly have a leucocyte-activating impact, most significant for Ap4A, considering phosphate chain length, and for Up4A, considering the type of nucleosides. These results suggest that the pro-inflammatory effects of NpnN can contribute to the development of atherosclerosis, probably in the early stages of chronic kidney disease, but their chemical composition affects their activity. © The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.