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.
- Journal of the American Society of Nephrology : JASN 22(9): 1696-706 (Journal)
- Registered Authors
- MeSH Terms
- Adenosine Triphosphate/analogs & derivatives
- Cell Proliferation
- Disease Models, Animal
- Epithelial Cells/metabolism
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Gene Knockdown Techniques
- Kidney Tubules, Proximal/metabolism
- MAP Kinase Signaling System
- Polycystic Kidney, Autosomal Dominant/etiology*
- Polycystic Kidney, Autosomal Dominant/metabolism
- Purinergic P2X Receptor Agonists
- Purinergic P2X Receptor Antagonists
- RNA, Messenger/metabolism
- Receptors, Purinergic P2X7/genetics
- Receptors, Purinergic P2X7/metabolism*
- 21636640 Full text @ J. Am. Soc. Nephrol.
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. (2011) Inhibition of the P2X7 Receptor Reduces Cystogenesis in PKD. Journal of the American Society of Nephrology : JASN. 22(9):1696-706.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes