# Renal AT2 Receptors in Hypertension

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $681,976

## Abstract

PROJECT SUMMARY/ABSTRACT
Hypertension (HT) affects ~48% of the US population. Increased renal sodium (Na+) retention is a major
contributor to the development of HT. The renal angiotensin type-1 receptor (AT1R), activated predominantly
by angiotensin (Ang) II, is both necessary and sufficient for inducing and sustaining HT during Ang II infusion.
Increased Na+ reabsorption in renal proximal tubule cells (RPTC) is a major determinant of this response. The
role of the angiotensin type-2 receptor (AT2R) in Na+ excretion and blood pressure (BP) control is less well
understood. AT2Rs are expressed in adult kidneys primarily in RPTC. Our past studies provided evidence for a
major role of RPT AT2Rs in the inhibition of renal Na+ reabsorption. Recently, we identified a defect in AT2R-
mediated natriuresis in spontaneously hypertensive rats (SHR) that pre-dates HT and can be circumvented by
direct renal administration of cyclic GMP (cGMP). Our results suggest that defective AT2R-induced natriuresis
may contribute to the pathogenesis of HT in SHR. The goals of this project are to (1) conclusively demonstrate
the role of AT2Rs in BP control using our newly developed RPTC-AT2R deficient mice, (2) identify downstream
AT2R signaling pathways mediating natriuresis, (3) characterize the primary RPTC AT2R defect(s) in SHR at
the cellular and molecular levels, and (4) validate renal cGMP and protein phosphatase 2A (PP2A) activation
as specific therapeutic targets for HT. These goals will be addressed under three specific aims: (1) To test the
hypothesis that RPT AT2Rs are required for the regulation of Na+ excretion and blood pressure; (2) To test the
hypothesis that protein phosphatase 2A (PP2A) initiates and sustains RPTC AT2R signaling to induce
natriuresis; and (3) To test the hypothesis that intrarenal PP2A activation and/or restoration of cGMP
levels/signaling can normalize blood pressure in hypertensive SHR and RPTC-selective AT2R knockout mice.
The project will apply a combination of state-of-the-art in vivo and cellular and molecular techniques to
determine mechanisms by which AT2R regulates Na+ excretion and BP. These studies will help define the
pathophysiology of HT and open the door to new classes of drugs for the treatment of human primary HT.

## Key facts

- **NIH application ID:** 10320944
- **Project number:** 5R01HL128189-06
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** ROBERT MUNSON CAREY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $681,976
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320944

## Citation

> US National Institutes of Health, RePORTER application 10320944, Renal AT2 Receptors in Hypertension (5R01HL128189-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320944. Licensed CC0.

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