RGD Reference Report - Knockout of P2rx7 purinergic receptor attenuates cyst growth in a rat model of ARPKD. - Rat Genome Database

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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.
RGD ID: 14995937
Pubmed: PMID:31630543   (View Abstract at PubMed)
PMCID: PMC6960783   (View Article at PubMed Central)
DOI: DOI:10.1152/ajprenal.00395.2019   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ATP export  IMP 14995937 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal renal filtration rate  IMP 14995937; 14995937 RGD 
decreased mean systemic arterial blood pressure  IMP 14995937; 14995937 RGD 
Objects Annotated

Genes (Rattus norvegicus)
P2rx7  (purinergic receptor P2X 7)
Panx1  (Pannexin 1)

Genes (Mus musculus)
Panx1  (pannexin 1)

Genes (Homo sapiens)
PANX1  (pannexin 1)

PCK-P2rx7em8Mcwi  (NA)

Additional Information