# Role of Renal and Intestinal AC6 and NHE3 for Phosphate Homeostasis

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $335,203

## Abstract

The precise regulation of the body's phosphate level is a critical task. Nearly all patients with chronic kidney
disease (CKD) exhibit hyperphosphatemia which is associated with increased cardiovascular mortality. Renal
reabsorption of Pi in the proximal tubule is hormonally regulated and requires fibroblast growth factor 23
(FGF23) and parathyroid hormone (PTH). The latter has been described to signal via cyclic adenosine
monophosphate (cAMP), generated by adenylyl cyclases (AC), and retrieve Na+-Pi cotransporters 2a and 2c
(Npt2a and Npt2c) and Na+/H+ exchanger 3 (NHE3) from the apical cell membrane. The overarching goal of
this proposal is to determine the roles of adenylyl cyclase 6 (AC6) and NHE3 in Pi homeostasis by analyzing
the intestine-kidney axis. We identified that AC6 is the most important isoform for PTH-mediated cAMP
formation and Pi homeostasis. In contrast to the expected pathophysiology resulting in impaired Pi excretion,
lack of AC6 causes renal Pi wasting with 80% of Npt2a residing in lysosomes. To avoid further Pi loss, PTH
and FGF23 levels would be expected to be suppressed; however, lack of AC6 is associated with significantly
elevated levels of both hormones indicating that this Pi loss cannot be countered hormonally. While regulation
of the milieu intérieur would require intestinal Pi uptake to be enhanced or unchanged, we found that lack of
AC6 causes an almost complete absence of intestinal Npt2b. This paradox highlights that AC6 plays a role in a
so far unidentified negative feedback loop that suppresses Pi regulating hormones. Since PTH also targets
NHE3, we generated a novel kidney-specific NHE3 knockout mouse to determine the contribution of NHE3 for
Pi homeostasis. While this model has normal Npt2a abundance, Npt2c abundance is diminished, providing a
novel link between NHE3 and Npt2c that has never been shown before. In Aim 1, we will determine the role of
renal AC6 in Pi homeostasis under normal conditions and CKD. In Aim 2, we will delineate the contribution of 3
specific signaling pathways for Pi homeostasis: i) Gαs protein coupled AC6/cAMP/protein kinase A; ii) Gαq/11
protein coupled phospholipase C(PLC)/inositol triphosphate/Ca2+/protein kinase C; and iii) FGF23. A novel
mouse model with defective PLC (named DSEL mouse) and AC6 signaling will allow us to study the
contribution of each of these pathways in regulating expression of Npt2a/c in the proximal tubule. To determine
the contribution of FGF23 signaling we will pharmacologically antagonize FGF23 via a novel neutralizing
antibody. Aim 3 will determine if there is a linkage between NHE3 and Npt2c for Pi homeostasis. Based on the
hypothesis that NHE3 is regulated by PTH, we will use our kidney-specific NHE3 knockout mouse to study
Npt2a/c trafficking and colocalization and determine to which extent NHE3 is required for renal Pi homeostasis.
Aim 4 will determine if AC6 and/or NHE3 play a role in intestinal Pi uptake and Pi homeostasis by utilizing novel
int...

## Key facts

- **NIH application ID:** 9944520
- **Project number:** 5R01DK110621-06
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Timo Rieg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,203
- **Award type:** 5
- **Project period:** 2017-02-02 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944520

## Citation

> US National Institutes of Health, RePORTER application 9944520, Role of Renal and Intestinal AC6 and NHE3 for Phosphate Homeostasis (5R01DK110621-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9944520. Licensed CC0.

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