title: Inhibition of the P2X7 receptor reduces cystogenesis in PKD.
abstract: 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.
authors.affiliation: Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Chang
authors.forename: Jenn-Kan
authors.initials: JK
authors.lastname: Lu
authors.forename: Ya-Chung
authors.initials: YC
authors.lastname: Tian
authors.forename: Yung-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Hung
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Huang
authors.forename: Yau-Hung
authors.initials: YH
authors.lastname: Chen
authors.forename: Mai-Szu
authors.initials: MS
authors.lastname: Wu
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Yang
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000818:Animals; D049109:Cell Proliferation; D002923:Cilia / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D020935:MAP Kinase Signaling System; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000209:etiology* / Q000378:metabolism; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D012333:RNA, Messenger / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles; D015027:Zebrafish
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D053583:Interleukin-1beta; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D012333:RNA, Messenger; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; C017199:2',3'-dialdehyde ATP; D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases