Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

Knockout of P2rx7 purinergic receptor attenuates cyst growth in a rat model of ARPKD.

Authors: Arkhipov, Sergey N  Potter, D'Anna L  Geurts, Aron M  Pavlov, Tengis S 
Citation: Arkhipov SN, etal., Am J Physiol Renal Physiol. 2019 Oct 21. doi: 10.1152/ajprenal.00395.2019.
Pubmed: (View Article at PubMed) PMID:31630543
DOI: Full-text: DOI:10.1152/ajprenal.00395.2019

The severity of polycystic kidney diseases depends on the counterbalancing of genetic predisposition and environmental factors exerting permissive or protective influence on cyst development. One poorly characterized phenomenon in the cystic epithelium is abnormal purinergic signaling. Earlier experimental studies revealed high importance of the ionotropic P2X receptors (particularly, P2X7) in the pathophysiology of the cyst wall. To study mechanisms of P2X7 involvement in cyst growth and the aspects of targeting these receptors in PKD treatment we performed a CRISPR/SpCas9-mediated global knockout of the P2rx7 gene in PCK rats, a model of autosomal recessive PKD (ARPKD). A single base insertion in exon 2 of the P2rx7 gene leads to lack of P2X7 protein in the renal tissues of homozygous mutant animals that did not affect their viability or renal excretory function. However, PCK.P2rx7-/- rats demonstrated slower cyst growth (but not formation of new cysts) in comparison to heterozygous and PCK.P2rx7+/+ littermates. P2X7 receptors are known to activate pannexin-1, a plasma channel capable of releasing ATP, and we here found that pannexin-1 expression in cystic epithelium is significantly higher than in non-dilated tubules. P2X7 deficiency reduces renal pannexin-1 protein expression and daily urinary ATP excretion. Patch-clamp analysis revealed that lack of P2X7 increases ENaC activity in renal tissues and restores impaired channel activity in cysts. Interpretation of our current data in the context of earlier studies strongly suggest that P2X7 contributes to cyst growth by increasing pannexin-1-dependent pathogenic ATP release into the lumen and reduction of sodium reabsorption across the cyst walls.

Annotation

Disease Annotations
Gene Ontology Annotations
Phenotype Annotations
Objects Annotated

Additional Information

 
CRRD Object Information
CRRD ID: 14995937
Created: 2019-11-01
Species: All species
Last Modified: 2019-11-01
Status: ACTIVE



NHLBI Logo

RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.