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

Abstract

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 α1- and α2-adrenergic agonists. [3H]-thymidine uptake was tested in human visceral glomerular epithelial cells (vGEC) and mitogen-activated protein kinase (MAPK42/44) activation in vGEC and kidney cortex. The involved P2-receptors were characterized pharmacologically and by RT-PCR. Results. Sympathetic nerve stimulation and α-adrenergic agonists induced release of ATP from human kidney cortex. Seventy-five percent of the ATP released originated from non-neuronal sources, mainly through activation of α2-adrenergic receptors. ATP (1 to 100 3mol/L) and related nucleotides (1 to 100 μmol/L) increased [3H]-thymidine uptake. The adenine nucleotides ATP, ATPγS, ADP and ADPβS were about equally potent. UTP, UDP and α,β-methylene ATP had no effect. ATP, ADPβS but not α,β-methylene ATP activated MAPK42/44. ATP induced MAPK42/44activation, and [3H]-thymidine uptake was abolished in the presence of the MAPK inhibitor PD 98059 (100 μmol/L). mRNA for P2X4,5,6,7and P2Y1,2,4,6,11were 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.