# HDAC-mediated regulation of endothelin and nitric oxide

> **NIH NIH P01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $548,862

## Abstract

PROJECT 3 SUMMARY
 Sodium homeostasis is critical for maintenance of normal blood pressure. The collecting duct (CD) is
integral to the physiological regulation of natriuresis through control of CD Na+ transport processes. Our PPG
group has delineated that the ET-1/ETB pathway in the CD is a major component of controlling blood pressure
and Na+ homeostasis. Activation of the NOS/NO pathway in the CD is necessary for ET-1/ETB mediated
inhibition of Na+ reabsorption by the epithelial Na+ channel (ENaC) and subsequent Na+ excretion. The
mechanism of NOS activation, specifically the distinct activation of NOS1 and NOS3 isoforms, and the
relationship with the ET-1/ETB pathway in the CD are obscure. We discovered a novel high salt-induced
regulatory pathway mediated by histone deacetylase 1 (HDAC1). HDAC enzymes catalyze lysine deacetylation
of histones in the nucleus epigenetically regulating gene transcription. We found that high salt significantly
increases renal HDAC1 expression. Renal medullary infusion of an HDAC1 inhibitor in high salt fed rats
significantly increased blood pressure and blunted urinary ET-1 excretion. In preliminary studies, we found that
over-expression of HDAC1 in IMCD cells up-regulates ET-1 mRNA expression. Interestingly, HDAC1 is a
member of the molecular feedback loop of circadian transcriptional control genes, thus in coordination with
project 1 we will determine whether HDAC1 regulates ET-1 expression in a circadian manner. HDAC enzymes
also regulate lysine deacetylation of non-histone, cellular proteins in the cytosolic compartment. HDAC1
inhibition in rats on high salt diet also significantly reduced urinary NOx excretion. The CD, especially IMCD, is
exposed to 10-fold increases in flow with high salt intake compared to low salt intake. We find that flow-induced
NO production is Ca2+- and HDAC1-dependent in IMCD cells. Flow induces NOS1- and NOS3-derived NO
production in IMCD cells. We find that CD NOS1 is localized in the cytosolic compartment and directly interacts
with HDAC1. HDAC inhibition increases lysine acetylation of NOS1 without altering NOS1 expression in IMCD
cells. NOS3 is absent in the cytosolic compartment of IMCD, thus we propose that HDAC1 regulation of NOS3
activity is mediated indirectly. High salt induces Thr495NOS3 dephosphorylation mediating increased NOS3
activity. Our preliminary studies show that renal medullary HDAC1 inhibition prevents Thr495NOS3
dephosphorylation in high salt fed rats. Protein phosphatase 1 (PP1) is implicated in the dephosphorylation of
Thr495NOS3, thus we will determine whether HDAC1 activates PP1. The overall hypothesis is that high salt
increases Na+ excretion via activation of CD HDAC1 dependent up-regulation of CD ET-1/ETB signaling along
with NOS1 and NOS3 activity.

## Key facts

- **NIH application ID:** 10136713
- **Project number:** 5P01HL136267-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Jennifer S Pollock
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $548,862
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136713

## Citation

> US National Institutes of Health, RePORTER application 10136713, HDAC-mediated regulation of endothelin and nitric oxide (5P01HL136267-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136713. Licensed CC0.

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