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ZFIN ID: ZDB-PUB-110609-54
Inhibition of the P2X7 Receptor Reduces Cystogenesis in PKD
Chang, M.Y., Lu, J.K., Tian, Y.C., Chen, Y.C., Hung, C.C., Huang, Y.H., Chen, Y.H., Wu, M.S., Yang, C.W., and Cheng, Y.C.
Date: 2011
Source: Journal of the American Society of Nephrology : JASN   22(9): 1696-706 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Adenosine Triphosphate/analogs & derivatives
  • Animals
  • Cell Proliferation
  • Cilia/metabolism
  • Disease Models, Animal
  • Epithelial Cells/metabolism
  • Extracellular Signal-Regulated MAP Kinases/metabolism
  • Gene Knockdown Techniques
  • Humans
  • Interleukin-1beta/metabolism
  • Kidney Tubules, Proximal/metabolism
  • MAP Kinase Signaling System
  • Phenotype
  • Polycystic Kidney, Autosomal Dominant/etiology*
  • Polycystic Kidney, Autosomal Dominant/metabolism
  • Purinergic P2X Receptor Agonists
  • Purinergic P2X Receptor Antagonists
  • Pyridines
  • RNA, Messenger/metabolism
  • Receptors, Purinergic P2X7/genetics
  • Receptors, Purinergic P2X7/metabolism*
  • Tetrazoles
  • Zebrafish
PubMed: 21636640 Full text @ J. Am. Soc. Nephrol.
The P2X7 receptor participates in purinergic signaling, which may promote the progression of ADPKD. We examined the effects of a P2X7 receptor antagonist and a P2X7 receptor agonist on cyst development in a zebrafish model of polycystic kidney disease in which we knocked down pkd2 by morpholinos. We used live wt-1b pronephric-specific GFP-expressing zebrafish embryos to directly observe changes in the pronephros. Exposure of pkd2-morphant zebrafish to a P2X7 receptor antagonist (oxidized ATP [OxATP]) significantly reduced the frequency of the cystic phenotype compared with either exposure to a P2X7 receptor agonist (BzATP) or with no treatment (P < 0.01). Histology confirmed improvement of glomerular cysts in OxATP-treated pkd2 morphants. OxATP also reduced p-ERK activity and cell proliferation in pronephric kidneys in pkd2 morphants. Inhibition of P2X7 with an additional specific antagonist (A-438079), and through morpholino-mediated knockdown of p2rx7, confirmed these effects. In conclusion, blockade of the P2X7 receptor reduces cyst formation via ERK-dependent pathways in a zebrafish model of polycystic kidney disease, suggesting that P2X7 antagonists may have therapeutic potential in ADPKD.