# Significance of Epac signaling in renal Na+handling and hypertension

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $678,566

## Abstract

PROJECT SUMMARY
Kidneys play a central role in regulation of water-salt balance with excessive renal Na+ conservation being tightly
associated with hypertension. The existing diuretics inhibit Na+ reabsorption in individual renal tubule segments,
which often involves a compensatory response in other segments to limit their efficiency. Thus, targeting Na+
transporting systems in multiple segments simultaneously might represent a more effective way to fight
hypertension. Our groups generated abundant multicomponent evidence that exchange protein directly
activated by cAMP (Epac) isoforms 1 and 2 are critical regulators of renal Na+ handling in the proximal tubule
(PT) and the collecting duct (CD). Epac1 and Epac2 deletion compromises renal Na+ conservation in mice,
leading to reduced blood pressure during dietary Na+ restriction. This is associated with decreased activity and
expression of the sodium hydrogen exchanger-3 (NHE-3) in PT and epithelial Na+ channel (ENaC) in CD.
Furthermore, RNAseq Gene Ontology enrichment analysis revealed an improvement of mitochondria function
and reduction in the reactive oxygen species (ROS) production in PT and CD upon Epac deletion. Interestingly,
renal Epac expression is drastically increased during hypertension arguing for deleterious ramifications of Epac
over-activation in driving Na+ retention and the development of elevated blood pressure. To this end, we have
developed novel pharmacological tools to selectively inhibit Epac isoform(s), and observed natriuretic actions of
these small molecules while exhibiting low toxicity and potent bioavailability profiles. Overall, we hypothesize
that Epac1 and Epac2 isoforms are physiologically relevant regulators of sodium reabsorption in both PT and
CD in response to hypovolemia. On the contrary, over-activation of Epac cascade contributes significantly to
the development of renal sodium retention and hypertension, in part by increasing ROS production and oxidative
stress. We propose that pharmacological inhibition of Epac signaling could be a novel, potent, and safe strategy
to counteract hypertension and improve renal function. We plan to test this with 3 specific aims:
SA1. Determine salt-sensitivity associated with Epac-induced changes on tubular transport in mice
lacking Epac isoforms to establish roles of renal and extra-renal components of Epac signaling. SA2.
Examine the molecular targets and signaling mechanisms of Epac-dependent regulation of Na+ transport
in the PT and CD. SA3. To test the hypothesis that Epac1 and 2 are effective therapeutic targets of
hypertension using optimized Epac specific inhibitors.
In summary, we develop this proposal by merging highly complementary and synergistic expertise in renal
physiology/epithelial transport and Epac signaling/drug discovery from neighboring laboratories of Dr.
Pochynyuk and Dr. Cheng within the Department of Integrative Biology and Pharmacology, UTHSC at Houston.
We anticipate to uncover previously unrecog...

## Key facts

- **NIH application ID:** 10948044
- **Project number:** 1R01DK136462-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** XIAODONG CHENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,566
- **Award type:** 1
- **Project period:** 2024-08-19 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948044

## Citation

> US National Institutes of Health, RePORTER application 10948044, Significance of Epac signaling in renal Na+handling and hypertension (1R01DK136462-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10948044. Licensed CC0.

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