# The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis

> **NIH NIH R00** · AUGUSTA UNIVERSITY · 2020 · $21,087

## Abstract

PROJECT SUMMARY
Polycystic kidney diseases (PKD) are a group of inherited nephropathies characterized by the formation of fluid-
filled cysts along the nephron. Autosomal Recessive form of PKD (ARPKD) has an incidence of 1 in 20,000 live
births; infants with this disease that survive beyond the perinatal period develop chronic renal failure by
adolescence and eventually require kidney transplantation. This proposal focuses on the sodium transport
regulation in the renal collecting ducts in ARPKD and potential means of pharmacological intervention with the
cysts’ progression. Specifically, we have determined that Epithelial Sodium Channels (ENaCs), which are
expressed in the collecting ducts and represent the rate-limiting step of sodium reabsorption in this nephron
segment, are involved into the process of cystogenesis in the ARPKD setting. Our preliminary data indicate that
ENaC expression and activity are significantly lower in the cystic epithelial cells of a rat model of ARPKD, as
assessed with immunohistochemistry and single channel analysis in isolated cysts; furthermore, chronic
administration of the ENaC-specific inhibitor, benzamil, aggravated cyst formation. Using a novel enzymatic
microbiosensors approach we established that concentration of adenosine triphosphate (ATP) was significantly
higher in PCK rat cortical cysts compared to control rats. ATP was shown to inhibit ENaC via signaling cascades
initiated by binding to its receptors. Therefore, we hypothesized here that accumulation of excessive levels of
ATP in the lumen of the dilated collecting ducts affects specific purinergic receptors in the cystic cells and results
in ENaC inhibition; this suppresses normal sodium reabsorption in these collecting ducts, and promotes fluid
accumulation and cysts’ expansion. The integrative experimental approach used in this study will include single
nephron electrophysiology, in vivo animal studies, genetics, biochemistry, biosensors amperometry and confocal
microscopy and will address the clinically relevant problem of cyst expansion in ARPKD. Specifically, this
proposal will identify the receptors involved in the purinergic signaling in the cystic cells, and study the relevance
of ATP signaling to sodium reabsorption dependent on sodium content in the diet. This proposal will address the
following specific aims: 1. Determine the relationship between ENaC activity and cystogenesis in ARPKD; 2.
Elucidate the cellular and molecular mechanism by which excessive levels of ATP modulate sodium transport,
promoting cyst growth; and 3. Explore if P2 receptor agonists/antagonists and suppression of the ATP levels
can affect cystogenesis.

## Key facts

- **NIH application ID:** 10419229
- **Project number:** 7R00DK105160-06
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Daria Ilatovskaya
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $21,087
- **Award type:** 7
- **Project period:** 2018-02-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10419229

## Citation

> US National Institutes of Health, RePORTER application 10419229, The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis (7R00DK105160-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10419229. Licensed CC0.

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