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1 Epithelial Transport and Cell Biology Group, Dept. Physiology, UCL, London, United Kingdom; Nephrology, UCL, London, United Kingdom
2 Epithelial Transport and Cell Biology Group, Dept. Physiology, UCL, London, United Kingdom
3 Dept. of Biochemistry and Molecular Biology, UCL, London, United Kingdom
* To whom correspondence should be addressed. E-mail: c.turner{at}medsch.ucl.ac.uk.
P2Y receptors couple to G proteins and either mobilise intracellular Ca2+ or alter cAMP levels to modulate the activity of Ca2+- and cAMP-sensitive ion channels. We hypothesise that increased ion transport into the lumen of MDCK cysts can osmotically drive fluid movement and increase cyst size. Furthermore, activation of the adenylate cyclase/cAMP pathway may trigger cell proliferation via an extracellular signal-related kinase cascade. To test this hypothesis several P2Y receptor inhibitors were used on the MDCK in vitro model of renal cyst formation. The non-specific P2 receptor inhibitors Reactive blue 2 and suramin reduced cyst growth significantly, as did PPADS and, to a lesser extent, the P2Y1 specific antagonist MRS2179. Cyst growth was reduced by approximately 50% when ATP was removed from the culture medium with apyrase, although stable analogues of ATP failed to increase cyst size. The non-selective P2X receptor inhibitor Coomassie brilliant blue G was ineffective at reducing cyst growth, suggesting no involvement of P2X receptors. Finally, the presence of selective inhibitors of ERK activation (either PD98059 or U0126) greatly reduced cyst growth, whereas in untreated cysts ERK activity was observed to increase with time. We conclude that stimulation of endogenous P2Y receptors by extracellular ATP increases growth of MDCK cysts via cAMP-dependent activation of the ERK pathway. P2Y receptor antagonists may have therapeutic potential in reducing cyst size and slowing disease progression; although further studies in vitro and in vivo are needed to investigate the specificity and role of these P2Y receptors in renal cystic diseases.
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