The P2X7 ATP receptor modulates renal cyst development in vitro.
P2X(7), a purinergic receptor, is expressed in renal collecting ducts as they undergo fulminant cystogenesis in the cpk/cpk mouse model of autosomal recessive polycystic kidney disease (ARPKD). Dissociated cpk/cpk kidneys generate cysts from cell aggregates within 24h of suspension culture and we demonstrate that BzATP, a P2X(7) agonist, reduces cystogenesis. This effect is P2X(7)-specific, because: (i) equimolar concentrations of other purinergic agonists, ATP and UTP, had lesser effects and (ii) the P2X(7) inhibitor, oxidized ATP, abrogated the BzATP-mediated reduction in cystogenesis. BzATP did not significantly affect total cell number, proliferation, LDH release or caspase 3 activity, and zVAD-fmk, a caspase blocker, failed to modulate BzATP effects. In addition, this P2X(7) agonist did not significantly alter cyst size, probably excluding altered vectorial transport. In vivo, ATP was detected in cyst fluid from cpk/cpk kidneys; moreover, P2X(7) protein was also upregulated in human fetal ARPKD epithelia versus normal fetal collecting ducts. Thus, ATP may inhibit pathological renal cyst growth through P2X(7) signaling.
Hillman
Kate A
KA
Nephrology and Physiology, Royal Free Campus, Institute of Child Health, University College London, London, UK. kateh1@lineone.net
Woolf
Adrian S
AS
Johnson
Tanya M
TM
Wade
Angela
A
Unwin
Robert J
RJ
Winyard
Paul J D
PJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7
C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate