# Uncovering the Role of GPR39 in the kidney

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY
G-protein coupled receptors (GPCRs) are seven transmembrane domain receptors that make up the largest
class of proteins in the mammalian genome. When activated by an appropriate ligand, these receptors elicit
specific and coordinated cellular responses that dictate a wide variety of physiological processes. One such
receptor that I have begun to investigate is GPR39. While initial studies reported that zinc is the endogenous
ligand, more recent reports demonstrated that zinc acts as an allosteric potentiator of GPR39 signaling. Although
the endogenous ligand for GPR39 is still unclear, synthetic ligands have been key in understanding GPR39
signaling and have implicated functions for GPR39 in the heart, bone, skin, pancreas, and gastrointestinal tract.
However, despite its well-recorded abundance in the kidney, there have been no published studies into its role
in renal physiology. In preliminary data, I find that GPR39 localizes to principal cells (AQP2-positive) in the inner
medullary collecting duct, and data from our collaborators indicates that GPR39 activation influences renal water
handling. I therefore hypothesize that GPR39 activation inhibits water reabsorption by sequestering
AQP2 in sub-cellular compartments. In agreement with this hypothesis, I find that treatment of collecting duct
cells in vitro with a GPR39-specific agonist, cpd1324, altered dDAVP-induced AQP2 localization. Here, I propose
two Specific Aims to uncover the mechanistic role that GPR39 plays in renal water handling. In Aim 1, I will
examine three potential mechanisms by which GPR39 activation influences AQP2 trafficking in vitro. Aim 1A will
test whether GPR39 activation inhibits AVPR2 expression and activity, and Aims 1B/C will test whether GPR39
activation inhibits forward trafficking (Aim 1B) or promotes reverse trafficking of AQP2 (Aim 1C). In Aim 2, I will
determine the physiologic function of GPR39 in wild-type (WT) and knockout (KO) animals under conditions of
water restriction and rehydration after water restriction. To do this, I will quantify changes in parameters including
drinking volume, plasma sodium, urinary osmolality, and urinary output in WT and KO animals at baseline and
after intervention. In addition, I will perform molecular analyses on renal tissues to monitor changes in AQP2
expression, phosphorylation status, and localization. Together, the experiments in this proposal will provide key
insight into both the mechanism (Aim 1) and the physiological role (Aim 2) that GPR39 plays in kidney physiology.

## Key facts

- **NIH application ID:** 10901509
- **Project number:** 1F31DK137460-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mackenzie Kui
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-05-20 → 2026-05-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901509

## Citation

> US National Institutes of Health, RePORTER application 10901509, Uncovering the Role of GPR39 in the kidney (1F31DK137460-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10901509. Licensed CC0.

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