Characterization of purinergic receptor expression in ARPKD cystic epithelia

Oleg Palygin, Daria V. Ilatovskaya, Vladislav Levchenko, Christine A. Klemens, Lashodya Dissanayake, Anna Marie Williams, Tengis S. Pavlov, Alexander Staruschenko

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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 100 μM). 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 (α,β-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.

Original languageEnglish (US)
Pages (from-to)485-497
Number of pages13
JournalPurinergic Signalling
Volume14
Issue number4
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

Keywords

  • ARPKD
  • ATP
  • Intracellular calcium flux
  • Kidney
  • P2X
  • P2X
  • P2X receptors
  • P2rx4
  • P2rx7
  • PCK rat
  • Polycystic kidney disease
  • Purinergic receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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