Dinucleoside polyphosphates: newly detected uraemic compounds with an impact on leucocyte oxidative burst.
BACKGROUND
Dinucleoside polyphosphates (Np(n)N) 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 Np(n)N 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 (Ap(3)A) to diadenosine hexaphosphate (Ap(6)A) 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 (Up(4)A) and diadenosine tetraphosphate (Ap(4)A).


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, Ap(4)A, Ap(5)A and Ap(6)A enhanced lymphocyted-free radical production. In addition, Ap(3)A, Ap(4)A and Ap(5)A increased PMA-stimulated ROS production in lymphocytes. Monocytes and granulocytes parallel the lymphocyte response albeit with an inhibition of Ap(6)A on granulocytes. Considering Np(n)N with four phosphate groups, Up(4)A showed the most important stimulatory effects on monocytes and Ap(4)A on lymphocytes.


CONCLUSIONS
Np(n)N mainly have a leucocyte-activating impact, most significant for Ap(4)A, considering phosphate chain length, and for Up(4)A, considering the type of nucleosides. These results suggest that the pro-inflammatory effects of Np(n)N can contribute to the development of atherosclerosis, probably in the early stages of chronic kidney disease, but their chemical composition affects their activity.
Schepers
Eva
E
Renal Division, Department of Internal Medicine, University Hospital Ghent, Ghent, Belgium.
Glorieux
Griet
G
Jankowski
Vera
V
Dhondt
Annemieke
A
Jankowski
Joachim
J
Vanholder
Raymond
R
D002908:Chronic Disease; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014511:Uremia / Q000378:metabolism
D015226:Dinucleoside Phosphates; D017382:Reactive Oxygen Species; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013755:Tetradecanoylphorbol Acetate