# Pannexin-1/P2X7 interaction promotes excessive ATP release in kidney cysts and ADPKD progression via reduced NaCl reabsorption

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2021 · $400,209

## Abstract

PROJECT SUMMARY
 ADPKD (autosomal dominant polycystic kidney disease) is the most prevalent inherited progressive
kidney disease affecting 1:1000 live births in USA. Genetic predisposition is necessary for polycystic kidney
disease (PKD) initiation, although other, incompletely identified downstream processes 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 adenosine-3-phosphate (ATP) content in cysts. As a powerful regulator of
epithelial water-electrolyte transport, ATP can decrease reabsorption in the collecting duct system where ~70%
of ADPKD cysts develop. Particularly, as a paracrine agent, ATP limits activity of the epithelial sodium channel
(ENaC). Reduced ENaC activity is recognized as pivotal factors of cytogenesis. However, the mechanism of the
pathogenic ATP release and its role in Na+ transport during cyst development remains unclear.
 Pannexins are transmembrane proteins which were recently characterized to be capable of ATP release.
Interaction with P2X7 receptors promotes activation of pannexin-1 (PANX1) by forming high-conductive channels
serving as ATP-permeable pores. Our recently published and pilot data indicate that PKD cysts exhibit a unique
pathogenic situation when abnormally high level of both PANX1 and P2X7 express in cyst-lining cells.
 We hypothesize that the P2X7-dependent switching of pannexin-1 to the active form is the central
mechanism of ATP accumulation in the cysts and their growth. Our data suggest that luminal expression of both
PANX1 and P2X7 proteins dramatically increase in the human ADPKD cysts and in rodent models of PKD.
Moreover, pharmacological and genetic targeting of PANX1 channels and P2X7 receptors slows cyst growth.
 In the proposed project we plan to study if PANX1/P2X7 interaction contributes to ATP release in the
hypomorphic Pkd1RC/RC mouse model of ADPKD and how this mechanism reduces reabsorption across the cystic
epithelium. We will investigate Panx1 and P2rx7 expression during development of ADPKD. A set of experiments
involving patch-clamp is designed in cell cultures and native cysts to study regulation of PANX1-mediated ATP
release. As purinergic signaling is important for epithelial transport we will characterize calcium signaling and
ENaC function in freshly isolated cysts and normal collecting ducts. Breeding of Panx1 mutanat mice with
Pkd1RC/RC strain tests if genetic ablation of pannexin-1 inhibits cystogenesis by limiting ATP release and
improving sodium reabsorption. We also plan to study the potential of repurposing probenecid, a known gout
remedy and pannexin-1 blocker, for ADPKD treatment.

## Key facts

- **NIH application ID:** 10119367
- **Project number:** 1R01DK123266-01A1
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Tengis S Pavlov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $400,209
- **Award type:** 1
- **Project period:** 2021-06-03 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119367

## Citation

> US National Institutes of Health, RePORTER application 10119367, Pannexin-1/P2X7 interaction promotes excessive ATP release in kidney cysts and ADPKD progression via reduced NaCl reabsorption (1R01DK123266-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10119367. Licensed CC0.

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