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Kidney Week

Abstract: SA-PO475

ATP Release into Renal Cysts Via Pannexin-1/P2X7 Channels Decreases ENaC Activity

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Arkhipov, Sergey N., Henry Ford Health System, Detroit, Michigan, United States
  • Pavlov, Tengis S., Henry Ford Health System, Detroit, Michigan, United States
Background

Genetic predisposition is necessary for polycystic kidney disease (PKD) initiation, although there are other, incompletely identified downstream processes that are required for cyst growth. Their characterization may provide a unique opportunity for clinical interventions. One of the poorly studied phenomena in PKD is high ATP content in cysts. Unfortunately, neither origins of uncontrolled ATP release, nor consequences of abnormal purinergic signaling in relation to epithelial transport are well explored in the polycystic kidney.

Methods

We tested the distribution of pannexin-1 (Panx1) and P2X7, two proteins potentially involved in ATP release, in the kidneys of the Pkd1RC/RC mice, a model of autosomal dominant PKD (ADPKD). To establish if pannexin-1 contributes to ATP release in the collecting ducts (CD), we measured luminal accumulation of ATP in M1 cell renal CD monolayers. Also, single channel patch clamp analysis of polarized M1 cells was employed to study how P2X stimulation affects ENaC activity.

Results

Abundance of both Panx1 and P2X7 proteins were abnormally increased in the cyst lining cells compared to non-dilated collecting ducts. Mechanical stimulation increases ATP release by polirized M1 cells to the luminal side and this effect was significantely blunted by treatment with probenecid, a pannexin-1 blocker. Patch-clamp studies reveal that apical stimulation of P2X receptors with αβ-MeATP acutely reduces ENaC activity.

Conclusion

We conclude that in ADPKD progression, an abnormal hyperexpression of both PANX1 and P2RX7 occurs in the cyst lining epithelial cells. High abundance of both proteins is not typical for non-dilated CDs but, when happens in cysts, pannexin1/P2X7 cooperation elevates ATP release into the luminal space. High ATP level is a pathogenic factor facilitating cystogenesis by reducing ENaC-mediated reabsorption from the lumen.

Funding

  • NIDDK Support