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 alpha1- and alpha2-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 alpha-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 alpha2-adrenergic receptors. ATP (1 to 100 micromol/L) and related nucleotides (1 to 100 micromol/L) increased [3H]-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 MAPK42/44. ATP induced MAPK42/44 activation, and [3H]-thymidine uptake was abolished in the presence of the MAPK inhibitor PD 98059 (100 micromol/L). mRNA for P2X4,5,6,7 and P2Y1,2,4,6,11 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.
Vonend
Oliver
O
Department of Internal Medicine, University of Freiburg, Freiburg, Germany.
Oberhauser
Vitus
V
von Kügelgen
Ivar
I
Apel
Thomas W
TW
Amann
Kerstin
K
Ritz
Eberhard
E
Rump
Lars Christian
LC
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004558:Electric Stimulation; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007672:Kidney Cortex / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000166:cytology* / Q000294:innervation; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008934:Mitogens / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D009924:Organ Culture Techniques; D011810:Quinoxalines / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000502:physiology; D013936:Thymidine / Q000493:pharmacokinetics; D014316:Tritium
D000316:Adrenergic alpha-Agonists; D008934:Mitogens; D011810:Quinoxalines; D018048:Receptors, Purinergic P2; D014316:Tritium; D000068438:Brimonidine Tartrate; D000255:Adenosine Triphosphate; D013936:Thymidine; D009638:Norepinephrine