# Lysine Acetylation and the Regulation of Vasopressin/Aquaporin System in the Principal Cell

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $222,750

## Abstract

SUMMARY
Dysregulation of arginine vasopressin (AVP) and water channels, called aquaporins (AQPs), can lead to a variety
of clinically-significant water-electrolyte problems, ranging from severe dehydration to low plasma sodium. The
actions of AVP in the kidney are mediated via the AVP receptor 2 (AVPR2) predominantly on the kidney principal
cell. The AVP-sensitive water channels, AQP2 and AQP3, promote water reabsorption to prevent dehydration.
In doing so these water channels function to concentrate the urine. Based on our compelling preliminary data,
this proposal focuses on the first reported modification of AQP3, lysine 282 acetylation, in the regulation of
substrate permeability. Lysine acetylation is also important for gene expression and it is regulated via
acetyltransferases and deacetylases (HDACs) enzymes. We recently performed a systemic review and
metanalysis and determined that chronic HDAC inhibitor use, as occurs in the treatment of cancers, results in a
significant >2 odds ratio of experiencing fluid-electrolyte disorders in humans. Thus, determining the functional
significance of lysine acetylation in the kidney is critically important both from a physiological perspective and in
understanding the clinical impact of HDAC inhibition on water-electrolyte balance. Together, our compelling
preliminary data have led us to formulate the overarching hypothesis that regulation of the kidney AVPR2/AQP
axis by lysine acetylation is critical in regulating urinary concentrating ability and fluid balance. This will be tested
by the following two aims: Aim 1: To test the hypothesis that lysine acetylation of AQP3 increases substrate flux
in the principal cell promoting urine concentration. Aim 2: To test the hypothesis that HDAC1 and HDAC2
regulate the transcription of the AVPR2/AQP axis in the principal cell. We will combine unbiased, system biology
approaches with cell to whole animal experiments to close key gaps in our understanding of concentrating
mechanisms in the kidney and may reveal new therapeutic avenues to treat fluid-electrolyte disorders.

## Key facts

- **NIH application ID:** 10445263
- **Project number:** 5R01DK128001-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Kelly Hyndman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $222,750
- **Award type:** 5
- **Project period:** 2021-07-06 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445263

## Citation

> US National Institutes of Health, RePORTER application 10445263, Lysine Acetylation and the Regulation of Vasopressin/Aquaporin System in the Principal Cell (5R01DK128001-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10445263. Licensed CC0.

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