# Immune Mechanisms of Salt-Sensitive hypertension

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $579,579

## Abstract

Project Summary:
Salt-sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular mortality not only in
hypertensive, but also in normotensive adults. The diagnosis for SSBP is not feasible in the clinic due to lack of
a simple diagnostic test, making it difficult to investigate therapeutic strategies. Most research efforts to
understand the mechanisms of SSBP have focused on renal regulation of sodium (Na+). However, salt retention
or plasma volume expansion are not enhanced in salt sensitive (SS) versus salt resistant (SR) individuals. In
addition, over 70% of extracellular fluid is interstitial and therefore not directly controlled by renal salt and water
excretion. Thus, further research is needed to understand the extrarenal mechanisms contributing to SSBP.
We recently found that Na+ enters monocyte-derived dendritic cells through the amiloride sensitive epithelial Na+
channel (ENaC) and activates the NADPH oxidase leading to formation of highly reactive products of lipid
oxidation known as isolevuglandins (IsoLGs). IsoLGs adduct to self-proteins and act as neoantigens, which
activate T cells to produce cytokines that promote Na+ retention and blood pressure (BP) elevation. Interestingly,
analogous to SSBP, we found considerable variability in the response of human monocytes to in vitro exposure
to elevated Na+ which correlated with known cardiovascular risk factors. It is not known if this variability in the
responsiveness of monocytes to elevated Na+ happens in vivo and if it contributes to the SSBP.
Recent studies found that Na+ accumulates in the interstitium electrostatically bound to glycosaminoglycans but
can be mobilized. This is relevant to circulating monocytes as they enter and re-emerge from the interstitium with
increased ability to present antigens. Our data indicate that monocytes from humans with high skin Na+ are
activated and have increased IsoLGs. This R01 proposal presents an opportunity to study how immune activation
and interstitial Na+ interact to impact SSBP in well phenotyped SS and SR individuals. We hypothesize that
circulating monocytes transmigrate into regions of elevated Na+ including the skin, muscle and kidney, and are
activated via IsoLG-adduct formation leading to SSBP. In Aim 1, we will employ an inpatient Weinberger protocol
to classify participants as SS or SR and measure tissue Na+ using 23NaMRI to determine if tissue Na+ and
monocyte activation contribute to SSBP. In Aim 2, we will adoptively transfer monocytes with T cells from SS
and SR people into immunodeficient NSG-(KbDb)null (IA)null mice and determine if monocytes from humans with
SSBP induce T cell activation, endothelial dysfunction, end-organ damage and SSBP in the humanized mice.
These translational studies will advance the field and reveal more feasible and cost-effective diagnostic and
therapeutic strategies for SSBP. Our exciting preliminary data indicating that changes in monocyte IsoLGs mirror
changes in BP in ...

## Key facts

- **NIH application ID:** 10401485
- **Project number:** 5R01HL144941-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Annet Kirabo Kirabo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $579,579
- **Award type:** 5
- **Project period:** 2021-05-04 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401485

## Citation

> US National Institutes of Health, RePORTER application 10401485, Immune Mechanisms of Salt-Sensitive hypertension (5R01HL144941-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401485. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*