# Role of Proximal Tubule NHE3 in Angiotensin II-induced Hypertension

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $342,000

## Abstract

PROJECT SUMMARY
 In the United States, one in three adults will develop hypertension and require antihypertensive treatments
in their lifetime. More importantly, only 50% of patients with hypertension have blood pressure controlled with
current antihypertensive drugs. Poorly controlled hypertension is very prevalent in aging men and
postmenopausal women with impaired pressure natriuresis response. The factors contributing to poorly
controlled hypertension remain to be determined. It is clear, however, the development of all forms of
hypertension will require continuously resetting of the pressure natriuresis response to higher pressures.
Although previous studies have implicated the Na+/H+ exchanger 3 (NHE3) in the pressure natriuresis response
and angiotensin II (ANG II)-dependent hypertension, whether NHE3 in the proximal tubules of the kidney is
directly involved in the physiological pressure natriuresis response and its resetting in ANG II-induced
hypertension has never been specifically investigated previously. We have strong preliminary evidence that
conditional deletion of NHE3 selectively in the proximal tubules (PT-NHE3-KO), or pharmacological inhibition of
NHE3 selectively in the kidney, primarily in the proximal tubules, with a novel orally absorbable NHE3 inhibitor
significantly increases the pressure natriuresis response and attenuates ANG II- and salt-induced hypertension
by restoring pressure natriuresis response in mice. In this revised proposal, we will test the hypotheses that
NHE3 in the proximal tubules of the kidney is directly involved in the physiological pressure natriuresis
response and its resetting in ANG II-induced hypertension, and that pharmacological inhibition of NHE3
selectively in the kidney, primarily in the proximal tubules, will attenuate hypertension in animal models
of genetic-, ANG II-, aging-, and sex-associated hypertension by restoring pressure natriuresis
responses. In Specific Aim 1, we will test whether deletion of NHE3 selectively in the proximal tubules will
increase pressure natriuresis response and lower blood pressure by inhibiting proximal tubule Na+ reabsorption,
whereas upregulation, via overexpression, of NHE3 selectively in the proximal tubules will impair and reset
pressure natriuresis response to higher pressures by stimulating proximal tubule Na+ reabsorption and promoting
salt sensitivity of blood pressure. In a revised Specific Aim 2, we will test whether NHE3 in the proximal tubules
is directly involved in the physiological pressure natriuresis responses to acute saline volume expansion,
natriuretic peptides, or activation of AT2 receptor/NO/cGMP signaling, and in the resetting of pressure
natriuresis responses in ANG II-, L-NAME-, aging- and sex-associated hypertension. In Specific Aim 3, we will
test whether inhibition of NHE3 selectively in the kidney, primarily in the proximal tubules, with an orally
absorbable NHE3 inhibitor will attenuate genetic-, ANG II-, aging- and sex-associa...

## Key facts

- **NIH application ID:** 9934185
- **Project number:** 5R01DK102429-07
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Jia Long Zhuo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,000
- **Award type:** 5
- **Project period:** 2017-08-17 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934185

## Citation

> US National Institutes of Health, RePORTER application 9934185, Role of Proximal Tubule NHE3 in Angiotensin II-induced Hypertension (5R01DK102429-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934185. Licensed CC0.

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