ATP release in human kidney cortex and its mitogenic effects in visceral glomerular epithelial cells

Background. In chronic renal failure the sympathetic nervous system is activated. Sympathetic cotransmitters released within the kidney may contribute to the progression of renal disease through receptor-mediated proliferative mechanisms. Methods. In human renal cortex electrical stimulation induced adenosine 5'-triphosphate (ATP; luciferin-luciferase-assay) and norepinephrine (HPLC) release was measured. ATP release also was induced by alpha(1)- and alpha(2)-adrenergic agonists. [H-3]-thymidine uptake was tested in human visceral glomerular epithelial cells (vGEC) and mitogen-activated protein kinase (MAPK(42/44)) activation in vGEC and kidney cortex. The involved P2-receptors were characterized pharmacologically and by RT-PCR. Results. Sympathetic nerve stimulation and alpha-adrenergic agonists induced release of ATP from human kidney cortex. Seventy-five percent of the ATP released originated from nonneuronal sources, mainly through activation of alpha(2)-adrenergic receptors. ATP (I to 100 mumol/L) and related nucleotides (I to 100 mumol/L) increased [H-3]-thymidine uptake. The adenine nucleotides ATP, ATPgammaS, ADP and ADPbetaS were about equally potent. UTP, UDP and alpha,beta-methylene ATP had no effect. ATP, ADPbetaS but not alpha,beta-methylene ATP activated MAPK(42/44). ATP induced MAPK(42/44) activation, and [H-3]-thymidine uptake was abolished in the presence of the MAPK inhibitor PD 98059 (100 mumol/L), mRNA for P2X(4,5,6,7) and P2Y(1,2,4,6,11) were detected in human vGEC by RT-PCR. Conclusions. In human renal cortex, adrenergic stimulation releases ATP from neuronal and non-neuronal sources. ATP has mitogenic effects in vGEC and therefore the potential to contribute to progression in chronic renal disease. The pattern of purinoceptor agonist effects on DNA synthesis together with the mRNA expression suggests a major contribution of a P2Y1-like receptor.