# Role of PON3 in regulating renal Na+ and K+ homeostasis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $318,000

## Abstract

ABSTRACT
The mammalian paraoxonase (PON) family consists of three highly conserved members (PON1,
PON2 and PON3) with unique anti-oxidative and anti-atherosclerotic properties. PON1 and 2
have been implicated in blood pressure (BP) regulation. While the role of PON3 in regulating BP
has not been investigated, it is expressed in the aldosterone-sensitive distal nephron where the
fine tuning of Na+ absorption and K+ secretion occurs. PONs share key structural and functional
features with MEC-6, an endoplasmic reticulum-resident chaperone of C. elegans. MEC-6 is
required for proper folding, assembly, and surface expression of the mechanosensitive degenerin
channel in touch receptor neurons. The chaperon function is conserved between mammalian
PONs and C. elegans MEC-6. We have previously shown that both PON2 and PON3 regulate
functional expression of the epithelial Na+ channel (ENaC), a member of the ENaC/degenerin
family of ion channels. ENaC mediates the rate-limiting step of Na+ reabsorption in distal nephron
and has a key role in volume and BP control. While the constitutive K+ secretion is conducted by
the renal outer medullary K+ (ROMK) channels, ENaC-dependent and flow-induced K+ secretion
is mediated by the large conductance K+ (BK) channels. In the preliminary studies, we found that
Pon3 KO mice have higher ENaC activity and enhanced amiloride-sensitive natriuresis,
suggesting ENaC functional expression is upregulated in the absence of PON3. In addition, we
have identified BK channel as a novel target of PON3. When expressed in HEK293 cells, PON3
interacted with BK α subunit to reduce its surface expression and channel activity. Our proposed
studies will define mechanisms by which PON3 functions as a chaperone in the regulation of
ENaC and BK expression. We will determine the consequences of deleting PON3 in renal Na+
and K+ handling and BP control in mice. Successful completion our proposed studies will enhance
our understanding of the mechanisms by which PONs function as chaperones and their
physiological roles in kidney function and BP control.

## Key facts

- **NIH application ID:** 10489375
- **Project number:** 5R01DK130901-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Shujie Shi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $318,000
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489375

## Citation

> US National Institutes of Health, RePORTER application 10489375, Role of PON3 in regulating renal Na+ and K+ homeostasis (5R01DK130901-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10489375. Licensed CC0.

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