# Novel Target Mechanism (Renal Denervation) to Reduce Sodium Retention in Chronic Heart Failure

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $414,955

## Abstract

Project Summary
One hallmark feature of chronic heart failure (CHF) is sodium and fluid retention. While the cardio-renal
syndrome has been recognized, a comprehensive understanding of the precise cellular mechanisms
contributing to sodium and water retention in CHF remains elusive. Renal denervation (RDN) has been shown
to reduce sodium retention in rats and dogs with CHF. One of the key elements involved in renal sodium
retention is activation of epithelial sodium channels (ENaC) of principal cells in the collecting tubule. We have
previously shown that ENaC subunit expressions and activity were increased in the kidneys from rats with
CHF. We have recent evidence indicating that increased proteases in the tubular fluid may contribute to the
enhanced renal ENaC activity, providing a novel mechanistic insight for sodium retention commonly observed
in CHF. We have observed that in rats with CHF: 1) the levels of serine proteases were dramatically increased
in the urine; 2) protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic
responses to ENaC inhibitor benzamil in rats with CHF. Furthermore, our preliminary data have shown that
RDN decreased the levels of proteases in the urine, reduced protein expressions of ENaC subunits in the
kidney of CHF rats, supporting the potential role of sympathetic nerve activation. Based on these data, we will
test the hypothesis that RDN reduces renal sodium retention in CHF rats by modulation of the ENaC
and protease-ENaC axis. In AIM 1 we will determine the contribution of RDN in the expression/inactivation of
ENaC in rats with CHF rats. In AIM 2 we will determine the contribution of tubular proteases in activating ENaC
in rats with CHF. These aims will be addressed in rats with CHF using complementary methodologies ranging
from cellular to the whole animal level, including physiological measurement of sodium balance, ENaC activity,
eletrophysiological recording, protease and ubiquitination of ENaC using molecular biology techniques. The
successful completion of the proposed studies will provide significant new information and insight into the
contribution of ENaC regulation in altered sodium balance in CHF and the therapeutic benefits of RDN on
sodium fluid retention, endemic to CHF.

## Key facts

- **NIH application ID:** 10151456
- **Project number:** 5R01DK114663-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** KAUSHIK P PATEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $414,955
- **Award type:** 5
- **Project period:** 2017-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151456

## Citation

> US National Institutes of Health, RePORTER application 10151456, Novel Target Mechanism (Renal Denervation) to Reduce Sodium Retention in Chronic Heart Failure (5R01DK114663-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10151456. Licensed CC0.

---

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