Journal
PURINERGIC SIGNALLING
Volume 14, Issue 4, Pages 485-497Publisher
SPRINGER
DOI: 10.1007/s11302-018-9632-5
Keywords
ATP; PCK rat; Intracellular calcium flux; P2X receptors; Kidney; Polycystic kidney disease; ARPKD; P2rx7; P2rx4; P2X(7); P2X(4); Purinergic receptor
Categories
Funding
- National Institute of Health [R35 HL135749]
- Baltimore PKD Center PF Grant [R00 HL116603, P30 DK090868]
- PKD Foundation [221G18a]
- CVC A.O. Smith Fellowship
- American Heart Association [16EIA26720006, 17SDG33660149]
- Department of Veteran Affairs [I01 BX004024]
- [R00 DK105160]
- [T32 HL134643]
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Polycystic kidney diseases (PKDs) are a group of inherited nephropathies marked by formation of fluid-filled cysts along the nephron. Growing evidence suggests that in the kidney formation of cysts and alteration of cystic electrolyte transport are associated with purinergic signaling. PCK/CrljCrl-Pkhd1pck/CRL (PCK) rat, an established model of autosomal recessive polycystic kidney disease (ARPKD), was used here to test this hypothesis. Cystic fluid of PCK rats and their cortical tissues exhibited significantly higher levels of ATP compared to Sprague Dawley rat kidney cortical interstitium as assessed by highly sensitive ATP enzymatic biosensors. Confocal calcium imaging of the freshly isolated cystic monolayers revealed a stronger response to ATP in a higher range of concentrations (above 100M). The removal of extracellular calcium results in the profound reduction of the ATP evoked transient, which suggests calcium entry into the cyst-lining cells is occurring via the extracellular (ionotropic) P2X channels. Further use of pharmacological agents (,-methylene-ATP, 5-BDBD, NF449, isoPPADS, AZ10606120) and immunofluorescent labeling of isolated cystic epithelia allowed us to narrow down potential candidate receptors. In conclusion, our ex vivo study provides direct evidence that the profile of P2 receptors is shifted in ARPKD cystic epithelia in an age-related manner towards prevalence of P2X(4) and/or P2X(7) receptors, which opens new avenues for the treatment of this disease.
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