# Purinergic regulation of ENaC in the distal nephron

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $343,125

## Abstract

Summary
Discretionary control of renal Na+ transport matches renal Na+ excretion with dietary Na+ intake. Because Na+
excretion can influence blood pressure, disordered renal Na+ transport in many instances causes abnormal
blood pressure. Moreover, as we know from the actions of most diuretics and many tubulopathies interdiction
of normal renal Na+ transport changes blood pressure. Renal sodium excretion is fine-tuned in response to
hormonal signaling in the aldosterone-sensitive distal nephron (ASDN). Within the ASDN, the activity of the
epithelial Na+ channel, ENaC, is the principal mediator of Na+ reabsorption. Consequently, modulation of ENaC
activity is an important regulator of Na+ excretion and blood pressure. ENaC functions as one final effector of
the renin-angiotensin-aldosterone system (RAAS) during the control of blood pressure. Gain and loss of ENaC
function, like RAAS, increases and decreases blood pressure by decreasing and increasing renal Na+
excretion, respectively. Emerging evidence supports that there are other physiologically important signaling
pathways that function in parallel with the RAAS to fine-tune ENaC activity in the ASDN. Previous R01 funded
research from my laboratory demonstrated that a purinergic system intrinsic to the distal nephron regulates
ENaC activity through inhibitory paracrine signaling via apical membrane metabotropic P2Y2 receptors in
principal cells. Our findings have shown that this purinergic system is quantitatively important to the regulation
of ENaC and perhaps consequently, sodium excretion and blood pressure. The latter, though, is only surmised
having been tested indirectly and in a cursory manner. Similar to a gain of ENaC function, dysfunction of
normal paracrine purinergic inhibition of ENaC is predicted to cause salt-sensitivity and increases in blood
pressure as a result of inappropriate Na+ excretion. In contrast, activation of this system is predicted to
promote Na+ excretion. The studies proposed in this resubmission test the premise that inhibitory purinergic
regulation of ENaC contributes to the fine-tuning of renal Na+ excretion and consequently, regulation of blood
pressure. These studies will provide mechanistic understanding and offer a high degree of translation to the
human condition by testing the following three aims: 1) Determine if targeted disruption in the ASDN of
purinergic signaling increases ENaC activity, decreases Na+ excretion and causes salt-sensitivity; 2)
Determine if targeted activation of P2Y2 receptor signaling in the ASDN increases Na+ excretion and can
mitigate to some degree forced salt-sensitivity; and 3) Determine if inhibitory purinergic signaling is important
for ENaC regulation in the human kidney. It is expected that completion of these studies will elaborate a
physiologically important mechanism that contributes to the normal regulation of Na+ excretion; and that when
dysfunctional may cause certain forms of salt-sensitivity; and possibly serve as ...

## Key facts

- **NIH application ID:** 10132733
- **Project number:** 5R01DK113816-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** James D Stockand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $343,125
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132733

## Citation

> US National Institutes of Health, RePORTER application 10132733, Purinergic regulation of ENaC in the distal nephron (5R01DK113816-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132733. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*