2--3--dialdehyde-atp and Polycystic-Kidney--Autosomal-Dominant

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.

Topics: Adenosine Triphosphate; Animals; Cell Proliferation; Cilia; Disease Models, Animal; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Gene Knockdown Techniques; Humans; Interleukin-1beta; Kidney Tubules, Proximal; MAP Kinase Signaling System; Phenotype; Polycystic Kidney, Autosomal Dominant; Purinergic P2X Receptor Agonists; Purinergic P2X Receptor Antagonists; Pyridines; Receptors, Purinergic P2X7; RNA, Messenger; Tetrazoles; Zebrafish